bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–09–14
fifty-six papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Lipid droplets: Open questions and conceptual advances around a unique organelle.
  2. Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.
  3. PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer.
  4. Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer.
  5. Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer.
  6. Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
  7. An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
  8. Vitamin D Binding Protein, a Ligand of Integrin beta 1, Motivates Both Tumor Cells and Schwann Cells to Promote Perineural Invasion in Pancreatic Ductal Adenocarcinoma.
  9. ATG16L1 controls mammalian vacuolar proton ATPase.
  10. Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.
  11. Confinement, Jamming, and Adhesion in Cancer Cells Dissociating from a Collectively Invading Strand.
  12. Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
  13. Next-gen tools in cancer neuroscience.
  14. Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.
  15. Amino Acid Metabolism in Cancer Cachexia and Chemotherapy Myotoxicity.
  16. TurboID-based mapping of organelle membrane protein interactomes with digitonin-permeabilization.
  17. Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma.
  18. Elucidating cancer cachexia-mediated aberrant cardiac wasting signaling in human iPSC-derived cardiac muscle.
  19. Igf2 regulates early postnatal DPP4+ preadipocyte pool expansion.
  20. HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
  21. Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung cohort reveals new metastasis-associated copy-number alterations including frequent mutant-specific KRAS-allelic imbalance and identifies CDKN2A homozygous deletions as an independent biomarker of poor prognosis.
  22. Plasma membrane labelling efficiency, internalization and partitioning of functionalized fluorescent lipids as a function of lipid structure.
  23. An Autochthonous Model of Lung Cancer Identifies Requirements for Cellular Transformation in the Naked Mole-Rat.
  24. Single-Cell Membrane Molecular Cartography Enabled by Nanoengineered VUV-LDI Mass Spectrometry Imaging.
  25. The Effect of Cachexia on the Feeding Regulation of Skeletal Muscle Protein Synthesis in Tumour-Bearing Mice.
  26. 3D pattern formation of a protein-membrane suspension.
  27. Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices.
  28. PILS-Nir1 is a sensitive phosphatidic acid biosensor that reveals mechanisms of lipid production.
  29. Glycerol and glycerol-3-phosphate: multifaceted metabolites in metabolism, cancer and other diseases.
  30. DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.
  31. Influence of biologic sex and obesity on liver recurrence and survival in patients undergoing upfront surgery for pancreatic adenocarcinoma.
  32. Glucose restriction: double edged sword in cancer treatment.
  33. Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.
  34. Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids.
  35. Microautophagy: definition, classification, and the complexity of the underlying mechanisms.
  36. TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy.
  37. Loss of Skeletal Muscle Mass Is Associated With Reduced Cytotoxic T Cell Abundance and Poor Survival in Advanced Lung Cancer.
  38. Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics.
  39. Viscosity-sensitive fluorescent probes based on the hemicyanine for the organelle-specific visualization during autophagy and ferroptosis.
  40. An experimental workflow for investigating anoikis resistance in cancer metastasis.
  41. Scvi-hub: an actionable repository for model-driven single-cell analysis.
  42. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
  43. Structure and mechanism of the mitochondrial calcium transporter NCLX.
  44. Dynamic and precise electromagnetic levitation of single cells.
  45. Energy deficiency selects crowded live epithelial cells for extrusion.
  46. A sequence-activated near-infrared fluorescence probe for precisely tracking in vivo senescence.
  47. Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
  48. Amplifying antigen-induced cellular responses with proximity labelling.
  49. Flexible and robust cell-type annotation for highly multiplexed tissue images.
  50. Monitoring ferroptosis in vivo: Iron-driven volatile oxidized lipids as breath biomarkers.
  51. Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma.
  52. A Phase II Trial to Assess the Evolution of the KRAS Mutation Load by Liquid Biopsy in Patients With Resectable Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant NALIRIFOX.
  53. A brain center that controls consummatory responses.
  54. Functional synapses between neurons and small cell lung cancer.
  55. From Molecules to Modules: Advanced Characterization of Membrane Systems.
  56. The role of dynamic reciprocity in 3D cell migration: connecting cell and matrix mechanics to migratory plasticity.
  1. J Cell Biol. 2025 Oct 06. pii: e202406019. [Epub ahead of print]224(10):
    Lipid droplets: Open questions and conceptual advances around a unique organelle.
    W Mike Henne, Emma Reynolds, William A Prinz.
      Once viewed as mere lipid inclusions, the past four decades have witnessed an explosion of research into lipid droplet (LD) biogenesis and function. Pioneering cell biology, biochemical, genetics, and lipidomic studies now reveal LDs as active players in lipid metabolism and cellular homeostasis. Here, we discuss some of the major findings that defined LDs as bona fide organelles. However, despite what is known, much needs to be discovered. We highlight five enduring questions that continue to challenge the LD field and discuss a few misconceptions about this remarkable organelle.
    DOI:  https://doi.org/10.1083/jcb.202406019
  2. J Clin Invest. 2025 Sep 16. pii: e184172. [Epub ahead of print]
    Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis.
    Thomas Mandel Clausen, Ryan J Weiss, Jacob R Tremblay, Benjamin P Kellman, Joanna Coker, Leo A Dworkin, Jessica P Rodriguez, Ivy M Chang, Timothy Chen, Vikram Padala, Richard Karlsson, Hyemin Song, Kristina L Peck, Satoshi Ogawa, Daniel R Sandoval, Hiren J Joshi, Gaowei Wang, L Paige Ferguson, Nikita Bhalerao, Allison Moores, Tannishtha Reya, Maike Sander, Thomas C Caffrey, Jean L Grem, Alexandra Aicher, Christopher Heeschen, Dzung Le, Nathan E Lewis, Michael A Hollingsworth, Paul M Grandgenett, Susan L Bellis, Rebecca L Miller, Mark M Fuster, David W Dawson, Dannielle D Engle, Jeffrey D Esko.
      3-O-sulfation of heparan sulfate (HS) is the key determinant for binding and activation of Antithrombin III (AT). This interaction is the basis of heparin treatment to prevent thrombotic events and excess coagulation. Antithrombin-binding HS (HSAT) is expressed in human tissues, but is thought to be expressed in the subendothelial space, mast cells, and follicular fluid. Here we show that HSAT is ubiquitously expressed in the basement membranes of epithelial cells in multiple tissues. In the pancreas, HSAT is expressed by healthy ductal cells and its expression is increased in premalignant pancreatic intraepithelial neoplasia lesions (PanINs), but not in pancreatic ductal adenocarcinoma (PDAC). Inactivation of HS3ST1, a key enzyme in HSAT synthesis, in PDAC cells eliminated HSAT expression, induced an inflammatory phenotype, suppressed markers of apoptosis, and increased metastasis in an experimental mouse PDAC model. HSAT-positive PDAC cells bind AT, which inhibits the generation of active thrombin by tissue factor (TF) and Factor VIIa. Furthermore, plasma from PDAC patients showed accumulation of HSAT suggesting its potential as a marker of tumor formation. These findings suggest that HSAT exerts a tumor suppressing function through recruitment of AT and that the decrease in HSAT during progression of pancreatic tumorigenesis increases inflammation and metastatic potential.
    Keywords:  Cancer; Cell biology; Coagulation; Glycobiology; Oncology
    DOI:  https://doi.org/10.1172/JCI184172
  3. J Clin Oncol. 2025 Sep 10. JCO2500436
    PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer.
    Jennifer J Knox, Grainne O'Kane, Daniel King, Daniel Laheru, Amber N Habowski, Kenneth Yu, Kimberly Perez, Andrew J Aguirre, Zachary Coyne, Harry Harvey, Ronan A McLaughlin, Raymond W Jang, Robert C Grant, Elena C Elimova, Daniel J Renouf, Sandra Fischer, Kai Duan, Stephanie Ramotar, Gun Ho Jang, Amy Zhang, Craig E Devoe, Harshabad Singh, Michael J Pishvaian, Fieke E M Froeling, Wasif Saif, Eileen M O'Reilly, Erica S Tsang, Brian M Wolpin, Julie M Wilson, Anna Dodd, Trevor J Pugh, Xiang Y Ye, Steven Gallinger, David A Tuveson, Faiyaz Notta, Elizabeth M Jaffee.
       PURPOSE: To assess modified folinic acid/leucovorin, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX; mFFX) versus gemcitabine/nab-paclitaxel (GnP) in de novo metastatic pancreatic ductal adenocarcinoma (PDAC) and explore predictive biomarkers.
    PATIENTS AND METHODS: Patients were randomly assigned 1:1 to mFFX or GnP with exclusion of germline pathogenic variants in BRCA1/2 or PALB2. The primary end point was progression-free survival (PFS) between arms with 0.3 significance. The per-protocol (PP) population included patients who received one dose of chemotherapy. Pretreatment biopsies underwent whole-genome/transcriptome sequencing and patient-derived organoid (PDO) development, providing correlate recommendations at a molecular tumor board and outcomes assessed according to RNA signatures (basal-like v classical).
    RESULTS: Of 160 patients randomly assigned (80 mFFX, 80 GnP), 140 patients were in the PP population (71 mFFX, 69 GnP), with median follow-up of 8.3 months. The median PFS was 4.0 months for mFFX versus 5.3 months for GnP (hazard ratio [HR], 1.37 [95% CI, 0.97 to 1.92]; P = .069) in intention-to-treat. Median overall survival (OS) was 8.5 months with mFFX and 9.7 months with GnP (HR, 1.57 [95% CI, 1.08 to 2.28]; P = .017). Genomic data were generated in 94%, transcriptomes in 74%, and PDOs in 50%. The median PFS for those with basal-like was 3.0 (mFFX) and 5.5 (GnP) months (P = .17), and classical PDAC was 6.3 (mFFX) versus 5.4 (GnP) months (P = .36). The median OS in basal-like was 7.5 (mFFX) and 8.9 (GnP) months (P = .75) versus in classical OS was 9.7 (mFFX) and 13.9 (GnP) months (P = .047). Overall, 75 (54%) of patients received second-line treatment, 33/75 (44%) correlate-guided. The median time on second-line treatment was only 2.1 months with a median OS of 5.4 months for a correlate-guided choice versus 4.4 months on a standard chemotherapy approach (P = .45).
    CONCLUSION: In the phase II Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial population, PFS was similar between GnP and mFFX; however, OS and safety trends favored GnP. The second-line setting appears inadequate to offer precision choices, given the short survival observed.
    DOI:  https://doi.org/10.1200/JCO-25-00436
  4. Nat Cell Biol. 2025 Sep;27(9): 1543-1554
    Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer.
    Taslim A Al-Hilal, Maria-Anna Chrysovergi, Paula E Grasberger, Fei Liu, Vera Auernheimer, Yan Zhou, Zebin Xiao, Mark Anthony Leon-Duque, Alba Santos, Tamanna Islam, Matteo Ligorio, Delphine Sicard, Clemens K Probst, Vladimir Vrbanac, Tejaswini S Reddi, Ludovic Vincent, Cassandra Happe, Edward Chaum, Charles R Yates, Kaveh Daneshvar, Allan C Mullen, David Ting, Eric S White, Raghu Kalluri, Christina M Woo, Ellen Puré, Wolfgang H Goldmann, Jose Luis Alonso, Andrew M Tager, Adam J Engler, Daniel J Tschumperlin, David Lagares.
      Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)-paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FATL994E knock-in mouse, which disrupts FAK-paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK-paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01697-8
  5. Biochem Biophys Res Commun. 2025 Sep 06. pii: S0006-291X(25)01325-7. [Epub ahead of print]782 152609
    Maladaptive role of peridroplet mitochondria during lipophagy disruption in pancreatic cancer.
    Zhiheng Zhang, Liye Fang, Hiroki Furukawa, Andy Huang, Joshua Kranrod, John M Seubert, Kousei Ito, Shigeki Aoki.
      Pancreatic ductal adenocarcinoma (PDAC) cells exhibit high metabolic flexibility, enabling survival under glucose limitation by using alternative fuels such as fatty acids. Lipophagy, a selective form of autophagy targeting lipid droplets (LDs), supports mitochondrial respiration during such nutrient stress. Our previous study demonstrated that the LSD1 inhibitor SP-2509 disrupts lipophagy independently of LSD1 inhibition, leading to LD accumulation and ATP depletion in glycolysis-suppressed PDAC cells. However, the effects of disrupted lipid homeostasis on mitochondrial function remained unclear. Here, the effects of lipid overload on mitochondrial morphology and activity were investigated under glucose-restricted conditions. SP-2509 treatment caused substantial LD accumulation with mitochondrial fragmentation and closer LD-mitochondrion spatial proximity, forming peridroplet mitochondria (PDM)-like structures. These structures were not associated with increased fatty acid oxidation; instead, they correlated with impaired mitochondrial respiration, shown by a reduced complex II/IV activity ratio. Forced mitochondrial fission alone did not reduce ATP production, suggesting lipid metabolic disruption, rather than morphological changes, drives mitochondrial dysfunction. Moreover, mitochondria relocated from perinuclear to peripheral regions following treatment, a shift associated with reduced cell viability and indicating a possible link between nuclear-mitochondrial proximity and survival under stress. Our findings challenge the prevailing view of PDM as inherently adaptive organelles. In PDAC, aberrant PDM formation under lipid stress may represent a maladaptive response contributing to metabolic vulnerability. This newly identified dysregulation of lipid and mitochondrial homeostasis may offer a new therapeutic target in treatment-resistant pancreatic cancer.
    Keywords:  Lipid droplet; Lipophagy; Mitochondrial dysfunction; Pancreatic cancer; Peridroplet mitochondria
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152609
  6. J Biol Chem. 2025 Sep 08. pii: S0021-9258(25)02545-1. [Epub ahead of print] 110693
    Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
    Oliver J Newsom, Eric Zheng, Lucas B Sullivan.
      Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS. Here, we use a combination of live-cell imaging and quantitative lipidomics to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation, with serum metal and lipid components serving as crucial metabolic resources. Despite access to a wide range of lipid classes available in serum, we find albumin-bound lipids are the primary species consumed by cancer cells. Furthermore, we find that supplementing with additives that contain necessary metals and any of the albumin-associated lipid classes can obviate the FBS requirement for cancer cell proliferation. Using this defined system, we investigated cancer cell lipid consumption dynamics, finding that albumin-associated lipids are primarily consumed through a mass-action mechanism with minimal competition within or amongst lipid classes. We also find that lipid scavenging is a dominant lipid acquisition route and is necessary for cancer cell proliferation. This work therefore identifies metabolic contributions of serum and provides a framework for building defined culture systems that sustain cell proliferation without the undefined contributions of serum.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110693
  7. Nat Metab. 2025 Sep 08.
    An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Rachel 'Rae' J House, Althea Waldhart, Kelly H Sokol, Samuel R Daniels, Cameron J Lee, Joseph Longo, Amy Johnson, Vincent J Sartori, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse KrasG12D; Trp53-/- pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.
    DOI:  https://doi.org/10.1038/s42255-025-01366-y
  8. Adv Sci (Weinh). 2025 Sep 09. e11726
    Vitamin D Binding Protein, a Ligand of Integrin beta 1, Motivates Both Tumor Cells and Schwann Cells to Promote Perineural Invasion in Pancreatic Ductal Adenocarcinoma.
    Shan Zhang, Luju Jiang, Shuqi Cai, Zheqi Weng, Yuheng Zhu, Zhi-Wei Cai, Hui Li, Qing Li, Li-Peng Hu, Hong-Fei Yao, Rong Hua, Yu Zhao, Dongxue Li, Xiao-Mei Yang, Jun-Feng Zhang, Shu-Heng Jiang.
      Perineural invasion (PNI) is a common pathological characteristic of pancreatic ductal adenocarcinoma (PDAC), closely linked to postoperative recurrence, metastasis, and unfavorable prognosis. Nevertheless, the precise mechanisms that govern PNI in PDAC remain poorly elucidated. Here, group-specific component protein (GC) is identified as one of the most significantly upregulated genes related to PNI, primarily derived from malignant ductal cells compared to other cell types. GC knockdown attenuates PDAC cell invasiveness toward nerves, and this effect operates independently of vitamin D transport. Moreover, GC protein activates Schwann cells by inducing a dedifferentiation program, and enhances the mutual chemoattraction between PDAC cells and Schwann cells. Mechanistically, integrin β1 (ITGB1) serves as the functional receptor for GC protein in both PDAC and Schwann cells. Targeting the ITGB1-FAK signaling cascade proves effective in reducing PNI and Schwann cell activation. In KPC (Pdx-Cre; LSL-KrasG12D+; LSL-Trp53R172H/+) mice and orthotopic xenografts model, GC silencing and ITGB1 blockade both efficiently reduce cancer-nerve interactions and mitigate PDAC progression. Clinically, GC protein, ITGB1, and phosphorylated-FAK are positively associated with the severity of PNI in PDAC cases. Collectively, these data demonstrate that GC protein engages integrin receptor signaling to display distinct functions in cancer cells and Schwann cells, thus enabling PNI.
    Keywords:  VDBP; cancer neuroscience; neural invasion; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202511726
  9. J Cell Biol. 2025 Oct 06. pii: e202503166. [Epub ahead of print]224(10):
    ATG16L1 controls mammalian vacuolar proton ATPase.
    Thabata L A Duque, Masroor Paddar, Einar Trosdal, Ruheena Javed, Lee Allers, Michal H Mudd, Prithvi Akepati, Soumya R Mishra, Michelle Salemi, Brett Phinney, Shawn B Bratton, Thomas Wileman, Vojo Deretic.
      The mechanisms governing mammalian proton pump V-ATPase function are of fundamental and medical interest. The assembly and disassembly of cytoplasmic V1 domain with the membrane-embedded V0 domain of V-ATPase is a key aspect of V-ATPase localization and function. Here, we show that the mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. ATG16L1 knockout elevated V-ATPase activity, increased V1 presence on endomembranes, and increased the number of acidified intracellular compartments. ATG16L1's ability to efficiently bind V-ATPase was required for its inhibitory role in endolysosomal acidification and for control of Mycobacterium tuberculosis infection in mice. These findings uncover a hitherto unappreciated role of ATG16L1 in regulating V-ATPase, a key pump governing acidification and functionality of the endolysosomal system along with its physiological roles.
    DOI:  https://doi.org/10.1083/jcb.202503166
  10. Cancer Discov. 2025 Sep 08. OF1-OF18
    Extrachromosomal DNA-Driven Oncogene Spatial Heterogeneity and Evolution in Glioblastoma.
    Imran Noorani, Magnus Haughey, Jens Luebeck, Andrew Rowan, Eva Grönroos, Francesco Terenzi, Ivy Tsz-Lo Wong, Davide Pradella, Marta Lisi, Jeanette Kittel, Natasha Sharma, Chris Bailey, Clare E Weeden, Donald M Bell, Eric Joo, Vittorio Barbè, Matthew G Jones, King L Hung, Emma L Nye, Mary Green, Lucy Meader, Emma J Norton, Mark Fabian, Nnennaya Kanu, Mariam Jamal-Hanjani, Thomas Santarius, Andrea Ventura, James A R Nicoll, Delphine Boche, Howard Y Chang, Vineet Bafna, Weini Huang, Paul S Mischel, Charles Swanton, Benjamin Werner.
      Oncogenes amplified on extrachromosomal DNA (ecDNA) contribute to treatment resistance and poor survival across cancers. Currently, the spatiotemporal evolution of ecDNA remains poorly understood. In this study, we integrate computational modeling with samples from 94 treatment-naive human glioblastomas (GBM) to investigate the spatiotemporal evolution of ecDNA. We observe oncogene-specific patterns of ecDNA spatial heterogeneity, emerging from random ecDNA segregation and differing fitness advantages. Unlike PDGFRA-ecDNAs, EGFR-ecDNAs often accumulate prior to clonal expansions, conferring strong fitness advantages and reaching high abundances. In corroboration, we observe pretumor ecDNA accumulation in vivo in genetically engineered mouse neural stem cells. Variant and wild-type EGFR-ecDNAs often coexist in GBM. Those variant EGFR-ecDNAs, most commonly EGFRvIII-ecDNA, always derive from preexisting wild-type EGFR-ecDNAs, occur early, and reach high abundance. Our results suggest that the ecDNA oncogenic makeup determines unique evolutionary trajectories. New concepts such as ecDNA clonality and heteroplasmy require a refined evolutionary interpretation of genomic data in a large subset of GBMs.
    SIGNIFICANCE: We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene-specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs. See related article by Korsah et al., p. XX.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1555
  11. PRX Life. 2025 ;3(1):
    Confinement, Jamming, and Adhesion in Cancer Cells Dissociating from a Collectively Invading Strand.
    Wei Wang, Robert A Law, Emiliano Perez Ipiña, Konstantinos Konstantopoulos, Brian A Camley.
      When cells in a primary tumor work together to invade into nearby tissue, this can lead to cell dissociations-cancer cells breaking off from the invading front-leading to metastasis. What controls the dissociation of cells and whether they break off singly or in small groups? Can this be determined by cell-cell adhesion or chemotactic cues given to cells? We develop a physical model for this question, based on experiments that mimic aspects of cancer cell invasion using microfluidic devices with microchannels of different widths. Experimentally, most dissociation events ("ruptures") involve single cells breaking off, but we observe some ruptures of large groups (~20 cells) in wider channels. The rupture probability is nearly independent of channel width. We recapitulate the experimental results with a phase-field cell motility model by introducing three different cell states (follower, guided, and high-motility "leader" cells) based on their spatial position. These leader cells may explain why single-cell rupture is the universal most probable outcome. Our simulation results show that cell-channel adhesion is necessary for cells in narrow channels to invade, and strong cell-cell adhesion leads to fewer but larger ruptures. Chemotaxis also influences the rupture behavior: Strong chemotaxis strength leads to larger and faster ruptures. Finally, we study the relationship between biological jamming transitions and cell dissociations. Our results suggest unjamming is necessary but not sufficient to create ruptures.
    DOI:  https://doi.org/10.1103/prxlife.3.013012
  12. Int J Mol Sci. 2025 Aug 30. pii: 8466. [Epub ahead of print]26(17):
    Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
    Melvin Li, Sarah R Amend, Kenneth J Pienta.
      Metabolism is a tightly controlled, but plastic network of pathways that allow cells to grow and maintain homeostasis. As a normal cell transforms into a malignant cancer cell and proliferates to establish a tumor, it utilizes a variety of metabolic pathways that support growth, proliferation, and survival. Cancer cells alter metabolic pathways in different contexts, leading to complex metabolic heterogeneity within a tumor. There is an unmet need to characterize how cancer cells alter how they use resources from the environment to evolve, spread to other sites of the body, and survive current standard-of-care therapies. We review key techniques and methods that are currently used to study cancer metabolism and provide drawbacks and considerations in using one over another. The goal of this review is to provide a methods' guide to study different aspects of cell and tissue metabolism, how they can be applied to cancer, and discuss future perspectives on advancements in these areas.
    Keywords:  13C-metabolic flux analysis; Seahorse metabolic flux analysis; cancer metabolism; fluorescent probes; genetically encoded fluorescent biosensors; isotope tracing; untargeted metabolomics
    DOI:  https://doi.org/10.3390/ijms26178466
  13. Cell Rep. 2025 Sep 10. pii: S2211-1247(25)01029-0. [Epub ahead of print]44(9): 116258
    Next-gen tools in cancer neuroscience.
    Vera Thiel, Debpali Sur, Caroline C Picoli, Tamara McErlain, Katalina Couto, David J Simon, Yuan Pan, Karen Olivia Dixon, Rajan P Kulkarni, Sebastien Talbot, Alexander Birbrair.
      The emerging field of cancer neuroscience is rapidly evolving, driven by novel technologies and tools. These include advances in single-cell and spatial transcriptomics; genetic mouse models paired with automated high-throughput; and innovative optical electrophysiological approaches, optogenetics, chemogenetics, engineered viruses, and new methods for visualizing neuronal activity. Collectively, these technologies are revolutionizing how we investigate, manipulate, and characterize distinct components that contribute to the nervous system-cancer interface. In the present review, we discuss the key technologies that are closing the gap between oncology and neuroscience, highlighting the innovations that are propelling the cancer neuroscience field forward.
    Keywords:  CP: Cancer; CP: Neuroscience; cancer neuroscience; chemogenetics; imaging; optogenetics; transcriptomics; viral vectors
    DOI:  https://doi.org/10.1016/j.celrep.2025.116258
  14. Am J Physiol Cell Physiol. 2025 Sep 10.
    Pro-Fibrotic Immune Cells and Fibro-Adipogenic Progenitors Contribute to Skeletal Muscle Extracellular Matrix Remodeling and Fibrosis in Cancer Cachexia.
    Thomas D Cardaci, Arianna V Bastian, Kasie Roark, Brooke M Bullard, Mitchell M NeSmith, Christian A Unger, Robert L Price, Jason L Kubinak, E Angela Murphy, Brandon N VanderVeen.
      Cachexia, the loss of skeletal muscle mass and function with cancer, contributes to reduced life quality and worsened survival. Skeletal muscle fibrosis leads to disproportionate muscle weakness; however, the role of infiltrating immune cells and fibro-adipogenic progenitors (FAPs) in cancer-induced muscle fibrosis is not well understood. Using the C26 model of cancer cachexia, we sought to examine the changes to skeletal muscle immune cells and FAPs which contribute to excessive extracellular matrix (ECM) collagen deposition. CD2F1 male mice (n=35) were implanted with either 106 C26 or CT-26 (weight stable; WS) cells. Skeletal muscle immune cell populations, satellite cells, and FAPs were examined using high-dimensional flow cytometry. Skeletal muscle ECM ultrastructure was assessed via scanning electron microscopy (SEM) of decellularized muscle along with transmission electron microscopy (TEM). Cachectic mice had significant decreases in body weight (-13.4%, p=0.003) and skeletal muscle mass (-37%, p=0.006). Cachectic mice had elevated CD45+CD11b+Ly6g+ neutrophils compared to non-tumor bearing controls (128%, p=0.016) and elevated CD45+CD11b+Ly6g-F480+CD206+MHCII- profibrotic macrophages and increased CD45-Sca1+CD106+CD140a+ FAPs compared to WS (43%, p=0.014) and controls (59%, p=0.002) with thickening of the ECM, particularly of the endomysium and perimysium. SEM and TEM analysis also identified clusters of infiltrating cells localized to regions of excessive ECM deposition in cachectic mice that were absent in WS and controls. These data highlight changes to the muscle microenvironment which contribute to fibrosis and excessive ECM deposition in cancer cachexia. Targeting pro-fibrotic immune cells may represent a promising therapeutic approach to mitigate muscle wasting and dysfunction with cachexia.
    Keywords:  FAPs; atrophy; macrophages; muscle wasting; weakness
    DOI:  https://doi.org/10.1152/ajpcell.00448.2025
  15. Am J Physiol Cell Physiol. 2025 Sep 10.
    Amino Acid Metabolism in Cancer Cachexia and Chemotherapy Myotoxicity.
    Meghan V McCue, David A MacLean.
      Cancer induced skeletal muscle wasting (cachexia) is responsible for over 20% of cancer related deaths, yet much about the pathophysiology of the condition remains unknown. Importantly, cancer cachexia does not seem wholly responsive to traditional anabolic stimuli such as nutritional interventions. It is possible that tumours directly or indirectly target skeletal muscle for their dynamic and abundant pool of amino acids that can be reliably used by tumours to supplement energy production and biomass synthesis. Therefore, understanding how the presence of a tumour alters circulating and tissue level amino acid pools could provide valuable insight into tumour induced muscle wasting. The purpose of this review was to examine the current body of research that has studied amino acids in the context of cancer cachexia, to better understand how amino acids behave during the development of cancer, cachexia, and various cancer chemotherapies. Distinct heterogeneity was observed in the behaviour of amino acids when comparing weight stable vs. cachectic patients with cancer, and there may be important temporal considerations based on rhythmic changes in amino acid turnover and mealtimes. Overall, there was very little consistency in the reported fluctuations of amino acids from study to study, suggesting there may be heterogenous pathophysiology based on tumour type, stage, and patient age and co-morbidities. Further work is required to characterize longitudinal changes in amino acid metabolism with consideration for these factors. Enhancing our understanding of amino acid metabolism during cancer cachexia could provide opportunities for advancement in practical methodologies in cachexia research and treatment strategies.
    Keywords:  Amino Acid; Cachexia; Cancer; Muscle wasting; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00085.2025
  16. Biophys Rep. 2025 Aug 31. 11(4): 219-231
    TurboID-based mapping of organelle membrane protein interactomes with digitonin-permeabilization.
    Yang Sun, Lan Yang, Jingzi Zhang, Pu Tian, Shue Chen, Lei Fang, Zhi Hong.
      Protein-protein interactions at organelle membranes bridge organelles in close proximity, facilitating regulated metabolite exchange and maintaining cellular homeostasis. Enzyme-catalyzed proximity labeling (PL) has been widely used to uncover the molecular composition of these interactions, but excessive labeling of irrelevant cytosolic proteins complicates data analysis. To address this, we developed a streamlined protocol that combines the TurboID system with digitonin-permeabilization to efficiently map protein interactions at organelle membranes in live mammalian cells. Digitonin selectively permeabilizes the plasma membrane, removing cytosolic proteins while preserving the integrity of inner membranes like the ER and mitochondria. This approach enhances spatial resolution in proteo-mic analysis, enabling a more precise map for protein interactome. Using this method, we successfully achieved proximal labeling of ER-localized proteins REEP1 and REEP6 to decipher their interaction networks, demonstrating its applicability for studying membrane-associated interactions with greater clarity and reduced contamination.
    Keywords:  Digitonin-permeabilization; Organelle interactomes; Protein–protein interactions; Proximity labeling; REEP1/REEP6
    DOI:  https://doi.org/10.52601/bpr.2025.240051
  17. Oncogene. 2025 Sep 06.
    Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma.
    Samer Salem, Tiegang Han, Michel Alchoueiry, Nadine Mahmoud, Wafaa Bzeih, Joelle Chami, Damir Khabibullin, Hadi Mansour, Yan Tang, Thai H Ho, Jessalyn M Ubellacker, Carmen Priolo, Elizabeth P Henske.
      There are no proven therapies for metastatic or unresectable Chromophobe Renal Cell Carcinoma (ChRCC). ChRCC is characterized by high glutathione levels and hypersensitivity to ferroptosis, an iron-dependent form of cell death characterized by peroxidation of polyunsaturated fatty acids. The underlying mechanisms leading to ferroptosis hypersensitivity are unknown. Ferroptosis suppressor protein (FSP1) is a glutathione-independent suppressor of ferroptosis whose role in ChRCC is unexplored. In The Cancer Genomic Atlas (TCGA), we find that ChRCC exhibits the second highest upregulation of FSP1 relative to healthy organ out of all cancers, and that higher FSP1 expression correlates with poorer patient outcomes. We also define a ferroptosis signature combining FSP1 and Solute Carrier Family 7 Member 11 (SLC7A11) that predicts patient survival across all TCGA tumor types. Data queried from the Dependency Map and the Cancer Target Discovery and Development indicate that high FSP1 expression correlates with resistance to cell death induced by disruption of glutathione homeostasis via inhibition of glutathione peroxidase 4 (GPX4) or SLC7A11. Studies using ChRCC cell lines in vitro reveal that genetic inhibition of GPX4 or FSP1 individually does not induce substantial cell death, while inhibition of both results in near-complete loss of viability. Consistent with these genetic data, combining pharmacologic inhibition of GPX4 or SLC7A11 with inhibition of FSP1 demonstrates synergistic loss of viability. Strikingly, inhibition of FSP1 alone in vivo is sufficient to decrease ChRCC tumor growth by 69%, consistent with recent studies in lung and colorectal cancer showing similar effects. Taken together, these data establish FSP1 as targetable vulnerability in ChRCC.
    DOI:  https://doi.org/10.1038/s41388-025-03562-2
  18. bioRxiv. 2025 Sep 04. pii: 2025.08.18.670675. [Epub ahead of print]
    Elucidating cancer cachexia-mediated aberrant cardiac wasting signaling in human iPSC-derived cardiac muscle.
    Nora Hosny, Houda Cohen, Mohamed Waleed Elafany, Jeff Schreifels, John Bauer, Rishi Gulati, Brian R Thompson, Julia C Liu, Joseph M Metzger.
      Cancer cachexia is a highly debilitating clinical syndrome of involuntary body mass loss featuring profound muscle wasting leading to high mortality. Notably, cardiac wasting is prominent in cancer patients and cancer survivors. Cachexia studies present significant challenges due to the absence of human models and mainly short-term animal studies. To address this translational gap, we have developed a robust human-based cachexia experimental approach characterized by marked cardiac muscle wasting and contractile dysfunction, with increased expression of protein degradation markers. Using human iPSC-derived cardiac muscle, we investigated morphological, functional, and metabolic alterations in the key stages of cachexia and in the post-cachexia phase. C26 and HCT116 tumor cell lines were used to induce cachexia by two methods, pulse addition of cancer cell conditioned media or in transwell-adapted co-culture. Cachectic cardiac myocytes exhibited reduced contraction amplitude, prolonged relaxation time, and increased oxygen consumption rate (OCR), as assessed by video-based and Seahorse analyses. Mechanistic investigations centered on the Atrogin-1/Calcineurin A/NFAT axis revealed this signaling pathway as a central driver of cachexia-induced cardiac atrophy. Cachectic cardiac myocytes exhibited significant upregulation of Atrogin-1, leading to a marked decrease in Calcineurin A protein levels. This, in turn, impaired nuclear translocation of NFAT, thereby suppressing its transcriptional activity and downstream cell growth signaling. These molecular changes were accompanied by increased autophagic flux, as indicated by elevated LC3BII/LC3BI ratios. Furthermore, withdrawal of cachexia-inducing stimuli followed by regular media changes for one week led to normalization of Atrogin-1 and autophagy markers; however, functional impairments and metabolic dysregulation persisted, highlighting delayed recovery. Our new findings establish the Atrogin-1/Calcineurin A/NFAT axis as a key regulatory mechanism in cardiac muscle wasting and suggest this aberrant signaling axis may serve as a targetable mechanism for treatment of cachexia-induced cardiac dysfunction.
    DOI:  https://doi.org/10.1101/2025.08.18.670675
  19. Genes Dev. 2025 Sep 10.
    Igf2 regulates early postnatal DPP4+ preadipocyte pool expansion.
    Irem Altun, Khanh Ho Diep Vo, Safal Walia, Xiaocheng Yan, Inderjeet Singh, Ruth Karlina, Viktorian Miok, Lingru Kang, Valentin Kenneth Reichenbach, Andreas Israel, Dominik Lutter, Fabiana Perrochi, Siegfried Ussar.
      Adipose tissue is rapidly expanding early in life. Elucidating the queues facilitating this process will advance our understanding of metabolically healthy obesity. Using single-cell RNA sequencing, we identified compositional differences of prewean and adult murine subcutaneous adipose tissue. We identified a dipeptidyl peptidase-4 (Dpp4)-positive precursor population residing in the reticular interstitium of subcutaneous adipose expressing insulin growth factor 2 (Igf2) in prewean mice. We show that IGF2 drives proliferation rather than differentiation in these cells. Moreover, loss of Igf2 in Dpp4 + progenitor cells promotes adipogenesis. Our findings unravel the temporally restricted expression of Igf2 to promote preadipocyte expansion.
    Keywords:   adipose tissue development; DPP4+; IGF2; hyperplasia; preadipocyte; progenitor cells
    DOI:  https://doi.org/10.1101/gad.352710.125
  20. Cell. 2025 Sep 02. pii: S0092-8674(25)00929-8. [Epub ahead of print]
    HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
    Jeany Delafiori, Mohammed Shahraz, Andreas Eisenbarth, Volker Hilsenstein, Bernhard Drotleff, Alberto Bailoni, Bishoy Wadie, Måns Ekelöf, Alexander Mattausch, Theodore Alexandrov.
      Single-cell metabolomics (SCM) promises to reveal metabolism in its complexity and heterogeneity, yet current methods struggle with detecting small-molecule metabolites, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput SCM method combining cell preparation on custom glass slides, small-molecule matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (MS), and batch processing. We propose a unified framework covering quality control, characterization, structural validation, and differential and functional analyses. Profiling HeLa and NIH3T3 cells, we detected 73 small-molecule metabolites validated by bulk liquid chromatography tandem MS (LC-MS/MS), achieving high reproducibility and single-cell resolution. Interrogating nine NCI-60 cancer cell lines and HeLa, we identified cell-type markers in subpopulations and metabolic hubs. Upon inhibiting glycolysis in HeLa cells, we observed emerging glucose-centered metabolic coordination and intra-condition heterogeneity. Overall, we demonstrate how HT SpaceM enables robust, large-scale SCM across over 140,000 cells from 132 samples and provide guidance on how to interpret metabolic insights beyond population averages.
    Keywords:  LC-MS/MS; MALDI-imaging mass spectrometry; NCI-60; SpaceM; co-abundance; heterogeneity; high-throughput; reproducibility; single-cell metabolomics; small-molecule metabolites
    DOI:  https://doi.org/10.1016/j.cell.2025.08.015
  21. Br J Cancer. 2025 Sep 11.
    Molecular analysis of lung adenocarcinomas from the SAFIR02-Lung cohort reveals new metastasis-associated copy-number alterations including frequent mutant-specific KRAS-allelic imbalance and identifies CDKN2A homozygous deletions as an independent biomarker of poor prognosis.
    Abderaouf Hamza, Pierre Gestraud, Maryam Karimi, Alicia Tran-Dien, Laurène Syx, Sophie Vacher, Quentin Peretti, Ludovic Lacroix, Valery Attignon, Isabelle Soubeyran, Pascal Jézéquel, David Planchard, Samia Melaabi, Trenton Dailey-Chwalibóg, Marta Jimenez, Stefan Michiels, Nicolas Servant, Christophe Le Tourneau, Nicolas Girard, Fabrice André, Benjamin Besse, Maud Kamal, Fabrice Barlesi, Ivan Bièche.
       BACKGROUND: Identifying molecular alterations specific to advanced lung adenocarcinomas could provide insights into tumour progression and dissemination mechanisms.
    METHOD: We analysed tumour samples, either from locoregional lesions or distant metastases, from patients with advanced lung adenocarcinoma from the SAFIR02-Lung trial by targeted sequencing of 45 cancer genes and comparative genomic hybridisation array and compared them to early tumours samples from The Cancer Genome Atlas.
    RESULTS: Differences in copy-number alterations frequencies suggest the involvement in tumour progression of LAMB3, TNN/KIAA0040/TNR, KRAS, DAB2, MYC, EPHA3 and VIPR2, and in metastatic dissemination of AREG, ZNF503, PAX8, MMP13, JAM3, and MTURN. Conversely, no meaningful difference was found in pathogenic single-nucleotide variant frequencies, reinforcing the notion that they are early events in tumorigenesis. CDKN2A homozygous deletion was linked to poor clinical outcome in patients with early tumours (overall survival hazard ratio 2.17, 95% CI: 1.43-3.28, corrected p-value = 0.01). Furthermore, we found that KRAS mutant allele specific imbalance, i.e. focal amplification of the mutant allele, is more prevalent in locoregional or distant samples of metastatic patients than in early lesions (8.4%, 13% and 2.8% respectively). This observation was replicated in three public cohorts. Tumours with KRAS mutant allele specific imbalance show specific patterns of co-occurrence and mutual exclusion with alterations in key cancer genes like CDKN2A, TP53, STK11 and NKX2-1, often in a tumour type dependent manner.
    CONCLUSION: Advanced LUAD tumours exhibit higher copy-number alteration burden, with distinct alterations associated with tumour progression and metastasis. CDKN2A homozygous deletions predict poor prognosis in early disease, while KRAS mutant allele-specific imbalance is enriched in advanced tumours.
    DOI:  https://doi.org/10.1038/s41416-025-03183-2
  22. RSC Chem Biol. 2025 Sep 01.
    Plasma membrane labelling efficiency, internalization and partitioning of functionalized fluorescent lipids as a function of lipid structure.
    Erdinc Sezgin.
      Labeling the plasma membrane for advanced imaging remains a significant challenge. For time-lapse live cell imaging, probe internalization and photobleaching are major limitations affecting most membrane-specific dyes. In fixed or permeabilized cells, many membrane probes either lose signal after fixation or fail to remain localized to the plasma membrane. Thus, improved probes are critically needed for applications in spatial biology. In this study, we systematically compared a range of custom-synthesized and commercially available lipid-based probes for their efficiency in labeling the plasma membrane in live, fixed, and permeabilized cells. We identified a superior probe, which outperformed others due to its lipid structure. This comparison provides insights into ideal lipid probes for visualizing the plasma membrane using advanced imaging techniques.
    DOI:  https://doi.org/10.1039/d5cb00116a
  23. Cancer Discov. 2025 Sep 08.
    An Autochthonous Model of Lung Cancer Identifies Requirements for Cellular Transformation in the Naked Mole-Rat.
    Alyssa Shepard, Daniel K Lester, Scott Troutman, Sany Hoxha, Walid T Khaled, Ewan St J Smith, Thomas J Park, Rochelle Buffenstein, Dongliang Du, Mingxiang Teng, Christine M Dengler-Crish, Kenneth Y Tsai, Elsa R Flores, Andrea Ventura, Joseph L Kissil.
      There is growing interest in understanding the mechanisms underlying differences in cancer incidence among species (comparative oncology). The naked mole-rat (NMR) is often referenced as "cancer-resistant" and prior studies focused on identifying mechanisms explaining this. However, efforts to assess this in vivo have been limited. Herein, we provide evidence that the NMR presents as a novel autochthonous model of lung tumor initiation, driven by an introduction of the oncogenic Eml4-Alk fusion protein using CRISPR-mediated genome editing. Whereas in mice the inversion alone is sufficient to drive tumorigenesis, the inversion alone was insufficient to drive tumorigenesis in the NMR lung and tumor development required additional losses of the tumor suppressors p53 and pRb. Our findings suggest that the proposed "resistance" of the NMR to the development of cancer may reflect that the genetic events leading to tumor initiation are likely to be comparable to those present in human cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0526
  24. Anal Chem. 2025 Sep 08.
    Single-Cell Membrane Molecular Cartography Enabled by Nanoengineered VUV-LDI Mass Spectrometry Imaging.
    Cong-Lin Zhao, Ling-Ling Zhao, Bin Kang, Lei Xing, Han-Zhang Mou, Hong-Yuan Chen, Jing-Juan Xu.
      Deciphering the multicomponent of cell membranes at the single-cell level is critical for understanding pathological mechanisms such as tumor metastasis, yet remains technically daunting due to the membrane's nanoscale thickness and ultralow molecular abundance. Here, we introduce a surface-assisted vacuum ultraviolet laser desorption-ionization mass spectrometry imaging (SAVUVDI-MSI) platform that overcomes long-standing challenges of cytoplasmic interference and insufficient sensitivity. Leveraging the nanoscale depth profiling capability of VUV-LDI, we achieve precise ablation of a single-cell membrane. Coupled with self-engineered VUV-laser-cleavable Au-PEG-FA/Apt nanoprobes, the system not only provides nanoprobe-mediated specific recognition and signal conversion for target membrane protein but also enhances m/z signals originating from the cell membrane by 4-10-fold. This strategy permits simultaneous spatial mapping of phospholipids and cholesterol (via direct label-free imaging) and proteins (via nanoprobe targeting)─three key membrane components─without cytoplasmic overlap. Experimental validation confirmed the aberrant overexpression of proteins and cholesterol on cancer cell membranes. The integrated multivariate statistical analytical framework enables discrimination between cancerous and normal cells based on membrane molecular signatures, establishing a robust platform for nanoprobe-enhanced pathological screening with translational potential. This study marks the inaugural application of VUV laser-enhanced nanoprobes. The SAVUVDI-MSI platform establishes a foundation for the in situ monitoring of membrane heterogeneity in pathological processes.
    DOI:  https://doi.org/10.1021/acs.analchem.5c03479
  25. J Cachexia Sarcopenia Muscle. 2025 ;16(5): e70064
    The Effect of Cachexia on the Feeding Regulation of Skeletal Muscle Protein Synthesis in Tumour-Bearing Mice.
    Brittany R Counts, Quan Zhang, Jessica L Halle, Melissa J Puppa, Stephen E Alway, Junaith Mohamed, Jeremy P Loenneke, James A Carson.
       BACKGROUND: Cancer promotes muscle wasting through an imbalance in the tightly regulated protein synthesis and degradation processes. An array of intracellular signalling pathways, including mTORC1 and AMPK, regulate protein synthesis, and these pathways are responsive to the muscle's microenvironment and systemic stimuli. Although feeding and fasting are established systemic regulators of muscle mTORC1 and protein synthesis, the cancer environment's impact on these responses during cachexia development is poorly understood. Although the IL-6 cytokine family has been widely investigated as a driver of cachexia with several cancers, how this signalling regulates muscle responses to feeding and fasting requires further study. We investigated if the cancer environment alters the feeding and fasting regulation of skeletal muscle protein synthesis and if the IL-6 family of cytokines signalling through muscle glycoprotein 130 could regulate this response.
    METHODS: Male C57BL/6J mice were subcutaneously injected with 1 × 106 LLC cells or PBS. Mice were euthanized 25-30 days post-injection after a 12-h dark cycle fast, followed by access to food pellets for 1 h (fed) or immediately sacrificed. To determine AMPK and gp13's regulation of protein synthesis and anabolic signalling, we injected tamoxifen-inducible skeletal muscle AMPKa1a2 or gp130 knockout and floxed control mice with LLC cells or PBS. The gastrocnemius muscle was analysed for protein expression.
    RESULTS: Feeding increased p-rpS6 and protein synthesis in PBS (2.2- and 0.4-fold, p < 0.001) and LLC mice (1.7- and 0.9-fold, p < 0.001), but overall, LLC significantly reduced p-rpS6 and protein synthesis. Feeding only increased p-AKT in PBS mice (1.5-fold, p < 0.001). In vitro LLC-conditioned media did not inhibit the insulin induction of myotube p-AKT (p < 0.001) and p-rpS6 (p < 0.001). Muscle gp130 loss reduced the fasting p-AMPK induction in LLC mice but did not alter suppression of p-AKT and p-rpS6 and protein synthesis. Muscle AMPK loss increased p-rpS6 (2.1-fold, p < 0.001) and protein synthesis (0.7-fold, p < 0.001) in PBS mice but did not restore LLC-suppressed protein synthesis.
    CONCLUSIONS: Our study provides novel insight into muscle responsiveness to feeding and fasting in a cancer environment. We find the acute anabolic response to feeding is maintained during LLC-induced cachexia, whereas the fasting catabolic response is exacerbated. Muscle-specific gp130 loss prevented disrupted fasting AMPK activation but not protein synthesis. There is a need to understand the aberrant upstream and downstream regulation of muscle AMPK activity that is disrupted with cancer and leads to aberrant protein turnover regulation.
    Keywords:  anabolism; cancer; fasting; feeding; inflammation
    DOI:  https://doi.org/10.1002/jcsm.70064
  26. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2506401122
    3D pattern formation of a protein-membrane suspension.
    Amélie Chardac, Michael M Norton, Jonathan Touboul, Guillaume Duclos.
      Many essential cellular processes, including cell division and the establishment of cell polarity during embryogenesis, are regulated by pattern-forming proteins. These proteins often need to bind to a substrate, such as the cell membrane, onto which they interact and form two-dimensional (2D) patterns. It is unclear how the membrane's continuity and dimensionality impact pattern formation. Here, we address this gap using the MinDE system, a prototypical example of pattern-forming membrane proteins. We show that when the lipid substrate is fragmented into submicrometer-sized diffusive liposomes, adenosine triphosphate-driven protein-protein interactions generate three-dimensional (3D) spatially extended patterns, despite the complete loss of membrane continuity. Remarkably, these 3D patterns emerge at scales four orders of magnitude larger than the individual liposomes. By systematically varying protein concentration, liposome size, and density, we observed and characterized a variety of 3D dynamical patterns not seen on continuous 2D membranes, including traveling waves, dynamical spirals, and a coexistence phase. Simulations and linear stability analysis of a coarse-grained model revealed that the physical properties of the dispersed membrane effectively rescale both the protein-membrane binding rates and diffusion, two key parameters governing pattern formation and wavelength selection. These findings highlight the robustness of Min's pattern-forming ability, suggesting that protein-membrane suspensions could serve as an adaptable template for studying out-of-equilibrium self-organization in 3D, beyond in vivo contexts.
    Keywords:  membrane; pattern formation; protein
    DOI:  https://doi.org/10.1073/pnas.2506401122
  27. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2423875122
    Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices.
    Hongsheng Yu, Amit Pathak.
      During wound healing, tumor growth, and organ formation, epithelial cells migrate and cluster in layered tissue environments. Although cellular mechanosensing of adhered extracellular matrices is now well recognized, it is unclear how deeply cells sense through distant matrix layers. Since single cells can mechanosense stiff basal surfaces through soft hydrogels of <10 μm thickness, here we ask whether cellular collectives can perform such "depth-mechanosensing" through thicker matrix layers. Using a collagen-polyacrylamide double-layer hydrogel, we found that epithelial cell collectives can mechanosense basal substrates at a depth of >100 μm, assessed by cell clustering and collagen deformation. On collagen layers with stiffer basal substrates, cells initially migrate slower while performing higher collagen deformation and stiffening, resulting in reduced dispersal of epithelial clusters. These processes occur in two broad phases: cellular clustering and dynamic collagen deformation, followed by cell migration and dispersal. Using a cell-populated collagen-polyacrylamide computational model, we show that stiffer basal substrates enable higher collagen deformation, which in turn extends the clustering phase of epithelial cells and reduces their dispersal. Disruption of collective collagen deformation, by either α-catenin depletion or myosin-II inhibition, disables the depth-mechanosensitive differences in epithelial responses between soft and stiff basal substrates. These findings suggest that depth-mechanosensing is an emergent property that arises from collective collagen deformation caused by epithelial cell clusters. This work broadens the conventional understanding of epithelial mechanosensing from immediate surfaces to underlying basal matrices, providing insights relevant to tissue contexts with layers of varying stiffness, such as wound healing and tumor invasion.
    Keywords:  collagen; epithelial cells; extracellular matrix; mechanobiology; mechanosensing
    DOI:  https://doi.org/10.1073/pnas.2423875122
  28. J Cell Biol. 2025 Nov 03. pii: e202405174. [Epub ahead of print]224(11):
    PILS-Nir1 is a sensitive phosphatidic acid biosensor that reveals mechanisms of lipid production.
    Claire C Weckerly, Taylor A Rahn, Max Ehrlich, Rachel C Wills, Joshua G Pemberton, Michael V Airola, Gerald R V Hammond.
      Phosphatidic acid (PA) regulates lipid homeostasis and vesicular trafficking, yet high-affinity tools to study PA in live cells are lacking. We identified the lipin-like sequence of Nir1 (PILS-Nir1) as a candidate PA biosensor based on structural analysis of Nir1's LNS2 domain. Using liposome-binding assays and pharmacological and genetic manipulations in HEK293A cells expressing fluorescent PILS-Nir1, we found that while PILS-Nir1 binds PA and PIP2in vitro, only PA is necessary and sufficient for membrane localization in cells. PILS-Nir1 displayed greater sensitivity to organelle-generated PA than Spo20-based probes, enabling visualization of modest PA production by PLD downstream of muscarinic receptors-previously undetectable with existing biosensors. Thus, PILS-Nir1 provides a versatile, sensitive tool for real-time PA dynamics in live cells.
    DOI:  https://doi.org/10.1083/jcb.202405174
  29. Endocr Rev. 2025 Sep 10. pii: bnaf033. [Epub ahead of print]
    Glycerol and glycerol-3-phosphate: multifaceted metabolites in metabolism, cancer and other diseases.
    S R Murthy Madiraju, Elite Possik, Fahd Al-Mulla, Christopher J Nolan, Marc Prentki.
      Glycerol and glycerol-3-phosphate are key metabolites at the intersection of carbohydrate, lipid and energy metabolism. Their production and usage are organismal and cell type specific. Glycerol has unique physicochemical properties enabling it to function as an osmolyte, protein structure stabilizer, antimicrobial and antifreeze agent, important to preservation of many biological functions. Glycerol and glycerol-3-phosphate are implicated in many physiological and disease processes relating to energy metabolism, thermoregulation, hydration, skin health, male fertility, aging, and cancer. Glycerol has countless applications in the food, pharmaceutical and cosmetics industries. It is used as a sweetener, preservative, thickening agent, humectant, osmolyte and cryoprotectant. It is widely used in skin and wound care products, laxatives, in cell and tissue preservation and in medicines for numerous conditions. Here, we review the multiple uses and functions of glycerol and glycerol-3-phosphate and associated transporters, enzymes and target genes in health, senescence and disease. We discuss the evidence that glycerol may be present at much higher levels in tissues and cells than in the blood. We bring particular focus to the newly identified glycerol shunt in the direct formation of glycerol independent of lipolysis and as a pathway allowing cells to adapt to various stresses. Relevant to chronic metabolic diseases, cancer and aging, glycerol and glycerol-3-phosphate presents important translational implications and thus warrants much more attention.
    Keywords:  Energy metabolism; Glycerol metabolism; Glycerol shunt; Glycerol-3-phosphate; Glycerolipid cycle; Glyceroneogenesis
    DOI:  https://doi.org/10.1210/endrev/bnaf033
  30. Nat Genet. 2025 Sep;57(9): 2226-2237
    DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.
    TRACERx Consortium
      Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients.
    DOI:  https://doi.org/10.1038/s41588-025-02307-x
  31. Cancer. 2025 Sep 15. 131(18): e70088
    Influence of biologic sex and obesity on liver recurrence and survival in patients undergoing upfront surgery for pancreatic adenocarcinoma.
    Sean J Judge, Emily Manin, Joanne Chou, Robert J Torphy, Caitlin A McIntyre, Vinod P Balachandran, Michael I D'Angelica, Jeffrey A Drebin, Mithat Gönen, William R Jarnagin, T Peter Kingham, Eileen M O'Reilly, Wungki Park, Alice C Wei, Alice Zervoudakis, Kevin C Soares.
       BACKGROUND: The influence of obesity and sex on outcomes in pancreatic adenocarcinoma (PDAC) remains unclear. The association between obesity (body mass index [BMI], ≥30) and biologic sex (male or female) for outcomes in patients with PDAC undergoing a surgery-first approach was investigated.
    METHODS: A prospectively maintained pancreatic cancer database at the Memorial Sloan Kettering Cancer Center was queried to identify all patients undergoing surgery with a pathologic diagnosis of PDAC. Clinicodemographic variables, outcomes, and tumor mutational analyses for all available patients were collected. Cumulative incidence of first recurrence involving the liver was estimated via a cumulative incidence function. Multivariable Cox regression was used to investigate the association between BMI and sex for overall survival.
    RESULTS: From 2012 to 2022, 939 patients were identified who underwent surgery with a final pathologic diagnosis of PDAC. Median age was 70 years, 52% were male, and 24% were obese (BMI, ≥30). When dichotomized by sex and obesity status (BMI, <30 or ≥30), females with obesity had the lowest cumulative incidence of liver recurrence at 12 and 24 months postsurgery compared to all other groups (13% [95% CI, 7.2%-20%] and 15% [8.7%-23%], respectively). Females with obesity had the longest median overall survival at 37 months.
    CONCLUSIONS: After curative surgery for pancreatic cancer, females with obesity have a significantly lower rate of liver recurrence and the longest median overall survival. This does not appear to be related to surgical quality, receipt of adjuvant therapy, or tumor mutational profile. Investigation into host immune, metabolic, and hormonal parameters is paramount to understanding these differences.
    Keywords:  liver recurrence; obesity; pancreatic cancer; sex differences
    DOI:  https://doi.org/10.1002/cncr.70088
  32. Trends Cancer. 2025 Sep 05. pii: S2405-8033(25)00210-9. [Epub ahead of print]
    Glucose restriction: double edged sword in cancer treatment.
    Shenglong Xia, Dingjiacheng Jia.
      Glucose restriction generally limits tumor growth. Recently, Wu et al. reported that glucose restriction inhibits primary tumors but promotes lung metastasis by forming a macrophage-dominated, natural killer (NK) cell-deficient pre-metastatic niche (PMN). This finding provides a new perspective on understanding the dual role of glucose metabolism regulation in cancer treatment.
    Keywords:  cancer metastasis; exosomal TRAIL; low-carbohydrate diet; macrophages; natural killer cells; pre-metastatic niche
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.012
  33. Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01049-6. [Epub ahead of print]44(9): 116278
    Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.
    Deena B Snoke, Jos L van der Velden, Emma R Bellafleur, Jacob S Dearborn, Sean M Lenahan, Alexandra E Beal, Reem Aboushousha, Skyler C J Heininger, Jennifer L Ather, Madeleine M Mank, Hailey Sarausky, Daniel Stephenson, Julie A Reisz, Angelo D'Alessandro, Devdoot Majumdar, Thomas P Ahern, Kaiwen Xu, Kim L Sandler, Bennett A Landman, Yvonne M W Janssen-Heininger, Matthew E Poynter, David J Seward, Michael J Toth.
      Cancer cachexia (CC), a syndrome of skeletal muscle and adipose wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between preclinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell-specific KrasG12D/+ (G12D) mice. G12D mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. G12D mice demonstrate early loss of adipose, a phenotype that was apparent across numerous models of CC and translates to patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in CC, and adipose wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC.
    Keywords:  CP: Cancer; CP: Metabolism; inflammation; lipolysis; lung neoplasms; organoids; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.116278
  34. Mol Cell. 2025 Sep 03. pii: S1097-2765(25)00708-7. [Epub ahead of print]
    Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids.
    Yaqin Deng, Goncalo Vale, Yonggang Liang, Shaojie Cui, Shimeng Xu, Jeffrey G McDonald, Jin Ye.
      Although polyunsaturated phospholipids are vital for cellular functions, their overaccumulation renders cells vulnerable to ferroptosis. It remains unclear how cells exposed to excess polyunsaturated fatty acids (PUFAs) prevent their over-incorporation into phospholipids. Here, we identified a mechanism by which ubiquitin regulatory X domain-containing protein 8 (UBXD8), a fatty acid (FA)-interacting protein, prevents overaccumulation of phospholipids containing docosahexaenoate (DHA), one of the most abundant PUFAs in mammalian cells. UBXD8 binds to and activates 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which specifically incorporates DHA into phospholipids. Thus, cultured cells and mouse livers deficient in UBXD8 were resistant to ferroptosis because of reduced production of DHA-containing phospholipids. Excess unsaturated FAs, including DHA, through their interaction with UBXD8, disrupt the UBXD8/AGPAT3 complex, thereby inhibiting AGPAT3-catalyzed synthesis of DHA-containing phospholipids. This FA-sensing mechanism prevents overaccumulation of DHA-containing phospholipids in cells exposed to excess DHA, thus reducing the ferroptotic potency of DHA, a property that might contribute to the health benefits of this ω-3 PUFA.
    Keywords:  AA; AGPAT3; DHA; UBXD8; ferroptosis; phospholipids; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.023
  35. Autophagy. 2025 Sep 10.
    Microautophagy: definition, classification, and the complexity of the underlying mechanisms.
    Yasuyoshi Sakai, Christian Behrends, Ana Maria Cuervo, Jayanta Debnath, Masanori Izumi, Andreas Jenny, Maurizio Molinari, Shuhei Nakamura, Masahide Oku, Marisa S Otegui, Laura Santambrogio, Han-Ming Shen, Tomohiko Taguchi, Michael Thumm, Takashi Ushimaru, Zhiping Xie, Fulvio Reggiori.
      Recently, rapid progress in the field of microautophagy (MI-autophagy) revealed the existence of multiple subtypes that differ in both intracellular membrane dynamics and molecular mechanisms. As a result, a single umbrella term "microautophagy" has become too vague, even creating some confusion among researchers both within and outside the field. We herein describe different subtypes of MI-autophagic processes and propose a systematic approach for naming them more accurately.
    Keywords:  Atg proteins; ESCRT proteins; lysosome; microautophagy; vacuole
    DOI:  https://doi.org/10.1080/15548627.2025.2559687
  36. Biochim Biophys Acta Mol Cell Res. 2025 Sep 04. pii: S0167-4889(25)00159-4. [Epub ahead of print] 120054
    TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy.
    Pandian Nagakannan, Md Imamul Islam, Shakila Sultana, Soheila Karimi-Abdolrezaee, Eftekhar Eftekharpour.
      Ferroptosis is a recently discovered lytic form of cell death that is triggered by iron-driven excessive lipid peroxidation and depletion of glutathione and glutathione peroxidase-4 (GPX4). This form of cell death has been linked to a wide range of conditions from cancer to neurodegenerative diseases. Using murine hippocampal HT22 neurons, we aimed to investigate the underlying mechanisms of glutamate-mediated ferroptosis. A robust increase in Thioredoxin-Inhibiting Protein (TXNIP) prompted us to use genetic approaches and examine the role of this protein in ferroptosis in HT22 neurons, mouse embryonic fibroblasts, and Hela cells. Our results indicate that TXNIP is a key player in ferroptotic pathway, as its deletion conferred resistance to classic ferroptosis-inducing agents (erastin, RSL3, and ML210), while TXNIP overexpression increased their susceptibility to ferroptosis. Notably, TXNIP deletion protected cells from mitochondrial dysfunction induced by ferroptotic agents, independent of GSH and GPX4 levels. We further showed that TXNIP mediates ferroptosis through facilitating degradation of the iron-binding protein ferritin via NCOA4-mediated ferritinophagy. This resulted in elevated cytosolic labile iron levels, therefore amplifying lipid peroxidation, and promoting ferroptosis. Our findings suggest that TXNIP acts as a positive regulator of ferroptosis by modulating autophagy and iron availability. Targeting TXNIP might hold promise in developing drugs for diseases involving the ferroptotic pathway.
    Keywords:  Autophagy; Erastin; Glutamate; Iron; Lipid peroxidation; Lysosome; Mitochondria; RSL3
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120054
  37. J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70063
    Loss of Skeletal Muscle Mass Is Associated With Reduced Cytotoxic T Cell Abundance and Poor Survival in Advanced Lung Cancer.
    Xin Nie, Yan Sun, David P J van Dijk, Min Deng, Ralph Brecheisen, Zhaoqi Wang, Qingxin Xia, Steven M W Olde Damink, Sander S Rensen.
       BACKGROUND: Body composition alterations such as skeletal muscle (SM) loss in cancer patients are associated with poor survival. In turn, immune cell-driven pathways have been linked to muscle wasting. We aimed to investigate the relationship between body composition, tumour-infiltrating lymphocytes and survival in patients with advanced lung cancer.
    METHODS: We studied 200 patients with advanced lung cancer receiving immunotherapy (n = 81) or non-immunotherapy regimens (n = 119). Body composition including SM index (SMI) at baseline and longitudinal changes were assessed using computed tomography (CT) scans at the third lumbar vertebra. Associations between body composition parameters and overall survival (OS) were evaluated using Cox regression analysis. The median value of SMI, stratified by sex, was used as the cut-off to define groups with high and low baseline SMI. Stable SMI was defined by any increase or < 2% decrease per 100 days; loss of SMI was defined by ≥ 2% decrease per 100 days. Logistic regression analysis was applied to investigate the association between SMI and peripheral circulating immune cells. Tumour-infiltrating lymphocytes were identified by immunohistochemistry, and their relationship with SMI was evaluated.
    RESULTS: SMI loss was associated with shorter OS (whole cohort: HR = 2.314, 95% CI = 1.388-3.858, p = 0.001; immunotherapy cohort: HR = 3.028, 95% CI = 1.113-8.236, p = 0.03; non-immunotherapy cohort: HR = 2.298, 95% CI = 1.191-4.435, p = 0.013). Low baseline SMI was associated with higher CD3+ T cell abundance (OR = 1.240, 95% CI = 1.080-1.424, p = 0.002) but lower CD3+ CD8+ T cell abundance (OR = 0.862, 95% CI = 0.762-0.974, p = 0.018) in peripheral blood. Subsequent SMI loss during treatment was also significantly associated with higher CD3+ T cell counts (OR = 3.414, 95% CI = 1.301-8.961, p = 0.013) and lower CD3+ CD8+ T cell abundance (OR = 0.666, 95% CI = 0.459-0.968, p = 0.033). Patients with stable SMI had a higher number of CD8+ tumour-infiltrating lymphocytes than patients with SMI loss (15.4% vs. 7.9%, p = 0.036).
    CONCLUSION: SM loss is an independent predictor for survival in patients with advanced lung cancer and is associated with reduced peripheral and tumour-infiltrating cytotoxic T cell abundance. An inadequate antitumour immune response may contribute to metabolic tissue wasting in cancer.
    Keywords:  TILs; cytotoxic T cell; lung cancer; skeletal muscle mass; survival
    DOI:  https://doi.org/10.1002/jcsm.70063
  38. Nat Commun. 2025 Sep 12. 16(1): 8268
    Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics.
    Anastasia Sosenko Piscitello, Ann-Sofie Nilsson, Michael Hawgood, Abid H Sayyid, Vasilis S Dionellis, Giovanni Giglio, Bruno Urién, Pratikiran Bajgain, Sotirios G Ntallis, Jiri Bartek, Thanos D Halazonetis, Bennie Lemmens.
      Cyclin-dependent kinases (CDKs) coordinate DNA replication and cell division, and play key roles in tissue homeostasis, genome stability and cancer development. The first step in replication is origin licensing, when minichromosome maintenance (MCM) helicases are loaded onto DNA by CDC6, CDT1 and the origin recognition complex (ORC). In yeast, origin licensing starts when CDK activity plummets in G1 phase, reinforcing the view that CDKs inhibit licensing. Here we show that, in human cells, CDK4/6 activity promotes origin licensing. By combining rapid protein degradation and time-resolved EdU-sequencing, we find that CDK4/6 activity acts epistatically to CDC6 and CDT1 in G1 phase and counteracts RB pocket proteins to promote origin licensing. Therapeutic CDK4/6 inhibitors block MCM and ORC6 loading, which we exploit to trigger mitosis with unreplicated DNA in p53-deficient cells. The CDK4/6-RB axis thus links replication licensing to proliferation, which has implications for human cell fate control and cancer therapy design.
    DOI:  https://doi.org/10.1038/s41467-025-63669-8
  39. Spectrochim Acta A Mol Biomol Spectrosc. 2025 Sep 02. pii: S1386-1425(25)01202-8. [Epub ahead of print]347 126895
    Viscosity-sensitive fluorescent probes based on the hemicyanine for the organelle-specific visualization during autophagy and ferroptosis.
    Wen-Pei Ni, Hui Wang, Qin Lin, Ru Sun, Jian-Feng Ge.
      The dynamic monitoring of cell death processes remains a significant challenge due to the scarcity of highly sensitive molecular tools. In this study, two hemicyanine-based probes (5a-5b) with D-π-A structures were developed for organelle-specific viscosity monitoring. Both probes exhibited correlation with the Förster-Hoffmann viscosity-dependent relationship (R2 > 0.98) and emitted near-infrared (NIR) fluorescence (652-666 nm). Key advantages of these probes included good photostability (retention over 92 %), minimal cytotoxicity (cell viability over 90 %), and an OFF-ON response to viscosity changes, confirming their suitability for continuous monitoring from physiological to pathological conditions. Moreover, probe 5a selectively targeted mitochondria (Pearson correlation coefficient (Pr) of 0.90) in a manner independent of mitochondrial membrane potential (MMP), while probe 5b localized to lysosomes (Pr = 0.90) independent of pH. In starvation and drug-induced autophagy models, probe 5a exhibited a 1.9-2.3-fold increase in fluorescence intensity. Furthermore, 5a monitored the gradual fusion of mitochondria with lysosomes, achieving a maximum colocalization coefficient of 0.78. Probe 5b demonstrated a 1.8-2.4-fold enhancement in fluorescence intensity during lysosomal autophagy. Additionally, in the ferroptosis process, probes 5a-5b exhibited 3.4-fold and 2.4-fold increase in fluorescence intensity in HeLa cells, showcasing the probes' real-time monitoring capabilities. These findings establish 5a-5b as versatile tools for studying autophagy and ferroptosis via mitochondrial and lysosomal viscosity dynamics, respectively.
    Keywords:  Autophagy; Ferroptosis; MMP-independent; Viscosity-sensitive; pH-independent
    DOI:  https://doi.org/10.1016/j.saa.2025.126895
  40. J Biol Methods. 2025 ;12(3): e99010066
    An experimental workflow for investigating anoikis resistance in cancer metastasis.
    Xue Han, Yipan Zheng, Xiaohui Si, Zhe Liu.
       Background: Anoikis is a form of programmed cell death triggered by the detachment of cells from the extracellular matrix. Anoikis resistance represents a critical factor in tumor metastasis, and elucidating the mechanisms by which epithelial cancer cells evade this process may provide a molecular insight for effectively targeting metastatic progression.
    Methods: Presented here are an experimental workflow and a detailed protocol to examine anoikis sensitivity in tumor cells both in vitro and in vivo. We described a detachment-induced anoikis model, a three-dimensional spheroid culture system, and an in vivo circulating tumor cell assay, by using the human lung carcinoma cell line A549 as a model system. We detailed the cell culture conditions, materials, and sample preparation, and the evaluation and quantification of anoikis. Together, these methods provide a comprehensive approach for investigating anoikis resistance.
    Conclusion: This protocol offers valuable insights into the mechanisms underlying anoikis resistance and may facilitate the identification of novel therapeutic targets for cancer treatment.
    Keywords:  Anoikis resistance; Cancer metastasis; Circulating tumor cell assay; Three-dimensional spheroid culture
    DOI:  https://doi.org/10.14440/jbm.2024.0140
  41. Nat Methods. 2025 Sep 08.
    Scvi-hub: an actionable repository for model-driven single-cell analysis.
    Can Ergen, Valeh Valiollah Pour Amiri, Martin Kim, Ori Kronfeld, Aaron Streets, Adam Gayoso, Nir Yosef.
      The growing availability of single-cell omics datasets presents new opportunities for reuse, while challenges in data transfer, normalization and integration remain a barrier. Here we present scvi-hub: a platform for efficiently sharing and accessing single-cell omics datasets using pretrained probabilistic models. It enables immediate execution of fundamental tasks like visualization, imputation, annotation and deconvolution on new query datasets using state-of-the-art methods, with massively reduced storage and compute requirements. We show that pretrained models support efficient analysis of large references, including the CZI CELLxGENE Discover Census. Scvi-hub is built within the scvi-tools open-source environment and integrated into scverse. Scvi-hub offers a scalable and user-friendly framework for accessing and contributing to a growing ecosystem of ready-to-use models and datasets, thus putting the power of atlas-level analysis at the fingertips of a broad community of users.
    DOI:  https://doi.org/10.1038/s41592-025-02799-9
  42. Nat Metab. 2025 Sep 09.
    Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism.
    Ran Liu, Zihan Zhang, Aye K Kyaw, Kariona A Grabińska, Hardik Shah, Hongying Shen.
      The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography-mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01358-y
  43. Nature. 2025 Sep 10.
    Structure and mechanism of the mitochondrial calcium transporter NCLX.
    Minrui Fan, Chen-Wei Tsai, Jinru Zhang, Jianxiu Zhang, Aswini R Krishnan, Tsung-Yun Liu, Yu-Lun Huang, Deniz Aydin, Siyuan Du, Briana L Sobecks, Madison X Rodriguez, Andrew H Reiter, Carolyn R Bertozzi, Ron O Dror, Ming-Feng Tsai, Liang Feng.
      As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes1-3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction4-9. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H+/Ca2+ exchanger, rather than as a Na+/Ca2+ exchanger as widely believed1. These findings provide critical insights into mitochondrial Ca2+ homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca2+.
    DOI:  https://doi.org/10.1038/s41586-025-09491-0
  44. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2512246122
    Dynamic and precise electromagnetic levitation of single cells.
    Malavika Ramarao, Victor Garcia-Gradilla, Mehmet Burcin Unlu, Ronald W Davis, Naside Gozde Durmus.
      The biophysical properties of single cells are crucial for understanding cellular function and behavior in biology and medicine. However, precise manipulation of cells in 3-D microfluidic environments remains challenging, particularly for heterogeneous populations. Here, we present "Electro-LEV," a unique platform integrating electromagnetic and magnetic levitation principles for dynamic 3-D control of cell position during separation. We demonstrated that small current adjustments in electromagnets significantly alter the levitation heights of diverse particles and cell types. By periodically modulating and tracking cell positions along the z-axis, Electro-LEV identified distinct levitation behaviors between single cells and cell clusters, with clusters responding more rapidly to magnetic field changes. Furthermore, we demonstrated that Electro-LEV significantly enhances the purity and efficiency of levitational sorting, achieving 10-fold enrichment of live cells from 50% starting viability samples and 18.8-fold enrichment from 10% starting viability samples. These results establish Electro-LEV as a powerful tool for investigating cellular heterogeneity, differentiating cell sizes and types, and improving cell sorting efficiency. Thus, Electro-LEV is broadly applicable, offering different possibilities for high-resolution cell analysis and label-free cell sorting in various biomedical fields, including but not limited to single-cell sequencing and drug screening.
    Keywords:  electromagnetic levitation; magnetic levitation; real-time control; single cells; sorting
    DOI:  https://doi.org/10.1073/pnas.2512246122
  45. Nature. 2025 Sep 10.
    Energy deficiency selects crowded live epithelial cells for extrusion.
    Saranne J Mitchell, Carlos Pardo-Pastor, Anastassia Tchoumakova, Thomas A Zangle, Jody Rosenblatt.
      Epithelial cells work collectively to provide a protective barrier, yet they turn over rapidly through cell division and death. If the numbers of dividing and dying cells do not match, the barrier can vanish, or tumours can form. Mechanical forces through the stretch-activated ion channel Piezo1 link both of the processes; stretch promotes cell division, whereas crowding triggers live cells to extrude and then die1,2. However, it was not clear what selects a given crowded cell for extrusion. Here we show that the crowded cells with the least energy and membrane potential are selected for extrusion. Crowding triggers sodium (Na+) entry through the epithelial Na+ channel (ENaC), which depolarizes cells. While those with sufficient energy repolarize, those with limited ATP remain depolarized, which, in turn, triggers water egress through the voltage-gated potassium (K+) channels Kv1.1 and Kv1.2 and the chloride (Cl-) channel SWELL1. Transient water loss causes cell shrinkage, amplifying crowding to activate crowding-induced live cell extrusion. Thus, our findings suggest that ENaC acts as a tension sensor that probes for cells with the least energy to extrude and die, possibly damping inadvertent crowding activation of Piezo1 in background cells. We reveal crowding-sensing mechanisms upstream of Piezo1 that highlight water regulation and ion channels as key regulators of epithelial cell turnover.
    DOI:  https://doi.org/10.1038/s41586-025-09514-w
  46. Chem Sci. 2025 Aug 28.
    A sequence-activated near-infrared fluorescence probe for precisely tracking in vivo senescence.
    Jiahuan Nong, Pengcheng Li, Mingming Zhu, Yifeng Li, Changsheng Wang, Yutao Zhang, Chenxu Yan, Zhiqian Guo.
      Real-time monitoring of senescent cells is of great significance for understanding and intervening in aging. Since overexpression of endogenous β-galactosidase (β-gal) is not unique to senescent cells, probes relying solely on β-gal activity could yield inaccurate senescent cell detection. Herein, we designed a dual-mode sequential response AND logic NIR probe MFB-βgal, which contains a β-gal-cleavable unit and a morpholine unit, serving as an enzymatic activity trigger and a lysosomal targeting moiety, respectively. MFB-OH is generated in situ after reaction with β-gal, which can detect the alkalinization of lysosomes by emission intensity in senescent cells. This probe has been successfully used to distinguish between SKOV-3 and senescent cells and applied to in vivo visualization of β-gal activity in a mouse model, providing a new strategy for the accurate detection of cellular senescence.
    DOI:  https://doi.org/10.1039/d5sc05331e
  47. EMBO J. 2025 Sep 08.
    Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
    Amanda L Gunawan, Irene Liparulo, Andreas Stahl.
      A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.
    Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-025-00549-3
  48. Nature. 2025 Sep 10.
    Amplifying antigen-induced cellular responses with proximity labelling.
    Shuojun Li, Yinghui Men, Zihan Wang, Yingcheng Wu, Hao Sun, Mingyang Yin, Xinrui Fan, Guiyun Deng, Zhicheng Yang, Tiange Yang, Yudian Xiao, Hu Zhou, Guangchuan Wang, Jia Fan, Chenqi Xu, Qiang Gao, Shuo Han.
      Antigen-induced clustering of cell surface receptors, including T cell receptors and Fc receptors, represents a widespread mechanism in cell signalling activation1,2. However, most naturally occurring antigens, such as tumour-associated antigens, stimulate limited receptor clustering and on-target responses owing to insufficient density3-5. Here we repurpose proximity labelling6, a method used to biotinylate and identify spatially proximal proteins, to amplify designed probes as synthetic antigen clusters on the cell surface. We develop an in vivo proximity-labelling technology controlled by either red light or ultrasound to covalently tag fluorescein probes at high density near a target antigen. Using T cell receptors as an example, we demonstrate that the amplified fluorescein effectively clusters and directs a fluorescein-binding bispecific T cell engager to induce enhanced T cell activation and cytotoxicity. Noninvasive, tissue-selective labelling in multiple syngeneic mouse tumour models produces potent immune responses that rapidly eradicate treated tumours. Efficient cell lysis further promotes epitope spreading to induce systemic immunity against untreated distal lesions and immune memory against rechallenge. Thus, proximity-labelling chemistry holds promise as a generalized strategy to manipulate antigen-dependent receptor function and cell states.
    DOI:  https://doi.org/10.1038/s41586-025-09518-6
  49. Cell Syst. 2025 Sep 08. pii: S2405-4712(25)00207-8. [Epub ahead of print] 101374
    Flexible and robust cell-type annotation for highly multiplexed tissue images.
    Huangqingbo Sun, Shiqiu Yu, Anna Martinez Casals, Anna Bäckström, Yuxin Lu, Cecilia Lindskog, Matthew Ruffalo, Emma Lundberg, Robert F Murphy.
      Identifying cell types in highly multiplexed images is essential for understanding tissue spatial organization. Current cell-type annotation methods often rely on extensive reference images and manual adjustments. In this work, we present a tool, the Robust Image-Based Cell Annotator (RIBCA), that enables accurate, automated, unbiased, and fine-grained cell-type annotation for images with a wide range of antibody panels without requiring additional model training or human intervention. Our tool has successfully annotated over 3 million cells, revealing the spatial organization of various cell types across more than 40 different human tissues. It is open source and features a modular design, allowing for easy extension to additional cell types.
    Keywords:  bioimage analysis; cell-type annotation; highly multiplexed imaging; machine learning; marker imputation; spatial proteomics; vision transformer
    DOI:  https://doi.org/10.1016/j.cels.2025.101374
  50. Redox Biol. 2025 Sep 02. pii: S2213-2317(25)00371-4. [Epub ahead of print]86 103858
    Monitoring ferroptosis in vivo: Iron-driven volatile oxidized lipids as breath biomarkers.
    Yuta Matsuoka, Yoshinori Katsumata, Po-Sung Chu, Rei Morikawa, Nobuhiro Nakamoto, Kohta Iguchi, Ken Takahashi, Tadayuki Kou, Ryo Ito, Kojiro Taura, Shujiro Yazumi, Hiroaki Terajima, Gen Honjo, Genki Ichihara, Yuki Muramoto, Kazuki Sato, Rae Maeda, Kazuhiro Hata, Naoya Toriu, Motoko Yanagita, Masaki Tajima, Sidonia Fagarasan, Ken-Ichi Yamada, Yuki Sugiura.
      Ferroptosis, an iron-dependent cell death mechanism characterized by excessive lipid peroxidation, has been implicated in numerous human diseases and organ pathologies. However, current detection methods necessitate invasive tissue sampling to assess lipid peroxidation, making noninvasive detection of ferroptosis in human subjects extremely challenging. In this study, we employed oxidative volatolomics to comprehensively characterize the volatile oxidized lipids (VOLs) produced during ferroptosis. Polyunsaturated fatty acid-derived VOLs were generated via iron-dependent LPO and released extracellularly as ferroptosis progressed. These VOLs were specifically generated during hepatic ferroptosis in mouse models of acetaminophen-induced liver injury and metabolic dysfunction-associated steatohepatitis (MASH) and were also detectable in the exhaled breath of patients with MASH. Specific VOLs released upon iron-dependent LPO are potential markers of ferroptosis in vivo and may facilitate noninvasive monitoring of cellular health in humans.
    Keywords:  Breath analysis; Ferroptosis; Liver disease; Volatile oxidized lipid
    DOI:  https://doi.org/10.1016/j.redox.2025.103858
  51. Cancer Immunol Res. 2025 Sep 08.
    Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma.
    Meredith L Stone, Veronica M Herrera, Yan Li, Heather Coho, Yuqing Xue, Kathleen Graham, Jennifer Ratmansky, Devora Delman, Shaun O'Brien, Gregory L Beatty.
      Pancreatic ductal adenocarcinoma (PDA) is defined by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., PD-1 and CTLA-4). Here, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that depletion of CSF1R+ myeloid cells in combination with anti-PD-1 and chemotherapy triggers T cell infiltration into PDA but causes compensatory remodeling of the myeloid compartment with limited tumor control. Unexpectedly, combined therapy against multiple myeloid targets including CSF1R, CCR2/5 and CXCR2 was insufficient to overcome treatment resistance. High-dimensional single cell analyses performed on T cell infiltrates in human and mouse PDA revealed upregulation of multiple immune checkpoint molecules, including PD-1, LAG-3, and CTLA-4. Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4+ and CD8+ T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0575
  52. Am J Clin Oncol. 2025 Sep 10.
    A Phase II Trial to Assess the Evolution of the KRAS Mutation Load by Liquid Biopsy in Patients With Resectable Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant NALIRIFOX.
    Rafael Álvarez-Gallego, Teresa Macarulla, Berta Laquente, Paloma Peinado, Florian Castet, Cesar Muñoz, Carles Fabregat-Franco, Lisardo Ugidos, Sharela Vega, Juli Busquets, Enrique Sanz-García, Carmen Toledano, Yolanda Quijano, Emilio Vicente, Antonio Cubillo.
       OBJECTIVES: To evaluate the association between the KRAS mutational load and the histologic tumor response in patients with resectable pancreatic ductal adenocarcinoma (PDAC) who received neoadjuvant treatment (NAC) with pegylated liposomal irinotecan in combination with oxaliplatin, 5-fluorouracil, and leucovorin (NALIRIFOX).
    METHODS: This was a multicenter, single-arm, interventional, open-label, phase 2 trial in patients 18 years or older who had histologically or cytologically confirmed PDAC and were candidates for surgery and received neoadjuvant NALIRIFOX. The primary outcome was determination of the association between the KRAS mutational load and the histologic tumor response after chemotherapy.
    RESULTS: Twenty patients were included in the study. Before initiating NAC, 11 patients were KRAS+, 6 were KRAS-, and 3 were not evaluable for KRAS mutation status. Eight of the 11 (72.7%) patients changed from KRAS+ at baseline to KRAS- after treatment, and none of the 6 (0.0%) patients changed from KRAS- at baseline to KRAS+ after treatment. A good histopathologic response after NAC was observed in 3 (15%) of the 20 patients, with a greater proportion of good responses among patients who were KRAS- (3 out of 16 [18.8%]) than among those who were KRAS+ (0 out of 1 [0.0%]) after NAC, although the differences were not statistically significant (P=0.633).
    CONCLUSIONS: Our results indicate that patients with potentially resectable PDAC tend to have detectable KRAS in the blood if the disease is locally more advanced and that most patients who are treated with neoadjuvant NALIRIFOX are negative for KRAS at the end of therapy.
    Keywords:  KRAS mutation status; NALIRIFOX; liposomal irinotecan; neoadjuvant chemotherapy; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1097/COC.0000000000001253
  53. Cell. 2025 Sep 04. pii: S0092-8674(25)00976-6. [Epub ahead of print]
    A brain center that controls consummatory responses.
    Jose A Canovas, Li Wang, Ahmed A M Mohamed, Larry F Abbott, Charles S Zuker.
      The innate attraction to sweet mediates appetitive and consummatory responses. Here, we dissected the circuit driving responses to sweet and showed that amygdala neurons tuned to sweet connect to the bed nucleus of the stria-terminalis (BNST) to promote sweet-evoked consumption. Next, we demonstrate that the BNST functions as a central hub, transforming appetitive signals into consumption and linking sensory inputs to the internal state, not only for sweet but also for other stimuli such as salt or food, to flexibly regulate consummatory behaviors. Using single-cell functional imaging, we show that ensemble activity in the BNST encodes stimulus identity and the animal's internal state. Finally, we demonstrate that manipulating BNST activity can bidirectionally transform consummatory responses. Together, these findings illustrate how the internal state modulates sensory responses, characterize a general brain dial for consumption, and provide fresh insights into sites of action of GLP1R agonists and a strategy to help promote weight gain in pathological states.
    Keywords:  GLP1R; brain circuits; cachexia; consummatory behaviors; internal state; sweet, salt, and food; taste; weight loss
    DOI:  https://doi.org/10.1016/j.cell.2025.08.021
  54. Nature. 2025 Sep 10.
    Functional synapses between neurons and small cell lung cancer.
    Vignesh Sakthivelu, Anna Schmitt, Franka Odenthal, Kristiano Ndoci, Marian Touet, Ali H Shaib, Abdulla Chihab, Gulzar A Wani, Pascal Nieper, Griffin G Hartmann, Isabel Pintelon, Ilmars Kisis, Maike Boecker, Naja M Eckert, Manoela Ianicelli Caiaffa, Olta Ibruli, Julia Weber, Roman Maresch, Christina M Bebber, Ali Chitsaz, Anna Lütz, Mira Kim Alves Carpinteiro, Kaylee M Morris, Camilla A Franchino, Jonas Benz, Laura Pérez-Revuelta, Jorge A Soriano-Campos, Maxim A Huetzen, Jonas Goergens, Milica Jevtic, Hannah M Jahn-Kelleter, Hans Zempel, Aleksandra Placzek, Alexandru A Hennrich, Karl-Klaus Conzelmann, Hannah L Tumbrink, Pascal Hunold, Joerg Isensee, Lisa Werr, Felix Gaedke, Astrid Schauss, Marielle Minère, Marie Müller, Henning Fenselau, Yin Liu, Alena Heimsoeth, Gülce S Gülcüler Balta, Henning Walczak, Christian Frezza, Ron D Jachimowicz, Julie George, Marcel Schmiel, Johannes Brägelmann, Tim Hucho, Silvia von Karstedt, Martin Peifer, Alessandro Annibaldi, Robert Hänsel-Hertsch, Thorsten Persigehl, Holger Grüll, Martin L Sos, Guido Reifenberger, Matthias Fischer, Dirk Adriaensen, Reinhard Büttner, Julien Sage, Inge Brouns, Roland Rad, Roman K Thomas, Max Anstötz, Silvio O Rizzoli, Matteo Bergami, Elisa Motori, Hans Christian Reinhardt, Filippo Beleggia.
      Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate1-3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41586-025-09434-9
  55. Adv Mater. 2025 Sep 12. e13056
    From Molecules to Modules: Advanced Characterization of Membrane Systems.
    Yaguang Zhu, Austin J Booth, Jamila G Eatman, Min A Kim, Yining Liu, Bidushi Sarkar, Bratin Sengupta, Xiaolin Yue, Chibueze V Amanchukwu, Seth B Darling, Jeffrey W Elam, Paul Fenter, Chong Liu, Kelsey B Hatzell.
      Membrane technologies can enhance the efficiency and selectivity of chemical separations in energy-water systems. Advanced characterization tools are critical for discerning separation mechanisms, revealing degradation processes, and designing novel materials and material systems for new and emerging challenges. The pursuit of next-generation membranes for water and energy applications requires understanding phenomena at the molecular scale, mesoscale, and macroscale. This perspective highlights advanced characterization techniques for elucidating and enhancing membrane performance, while addressing fundamental trade-offs involved in characterizing membranes under realistic conditions.
    Keywords:  characterization; low‐dimensional materials; membranes; synchrotrons
    DOI:  https://doi.org/10.1002/adma.202513056
  56. NPJ Biol Phys Mech. 2025 ;2(1): 21
    The role of dynamic reciprocity in 3D cell migration: connecting cell and matrix mechanics to migratory plasticity.
    Jacob J Duggan, Ryan J Petrie.
      While migratory cells can quickly change their mode of migration in complex three-dimensional environments, it is not clear why. Understanding the dynamic and reciprocal relationship migrating cells have with their microenvironments may help reveal why migratory plasticity, or mode-switching, is a common feature of eukaryotic cell motility. In this review, we discuss the physical and mechanical properties of cells and the environments they move through, and how those properties can influence each other. Given the dual role of the cytoskeleton in cell migration and cellular mechanics, we suggest that migratory plasticity derives from the necessity for the cell to maintain mechanical homeostasis in diverse physical environments.
    Keywords:  Biophysics; Cell biology
    DOI:  https://doi.org/10.1038/s44341-025-00027-1
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