bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–11–30
34 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Adherent cells sustain membrane tension gradients independently of migration.
  2. JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake.
  3. Interplay between cancer cell lipotypes and disease states.
  4. MicroCT enables simultaneous longitudinal tracking of murine pancreatic cancer progression and cachexia.
  5. Integrative analysis of genomic and transcriptomic data informs precancer progression in the pancreas.
  6. Iron addicted colorectal cancers exploit Heme-Complex II axis to resist oxidative cell death.
  7. Homeostatic regulation of intrinsic lipid curvature in eukaryotic cells.
  8. Fuel, form, and memory: The motility-driven journey of cancer cells.
  9. Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia.
  10. Imaging Cellular Metabolic Rewiring with SuMMIT-SRS.
  11. Cell size modulates ferroptosis susceptibility.
  12. Inhibition of oligomeric BAX by an anti-apoptotic dimer.
  13. Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
  14. Cellular mechanical properties in response to environmental viscosity imaged by Brillouin Microscopy.
  15. Soft Matter Physics Meets Cell Biology: Transitions of Collective Cell Migration in 3D Environments.
  16. Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
  17. Portioning organelles for autophagic clearance.
  18. When membrane proteins prefer lipids.
  19. Structural organization of p62 filaments and the cellular ultrastructure of calcium-rich p62-enwrapped lipid droplet cargo.
  20. ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling.
  21. Targeting macropinocytosis for cancer therapy.
  22. Downregulation of Sod2 increases atypical flat lesions and dysplasia to advance pancreatic ductal adenocarcinoma.
  23. ATG2 is a triglyceride transfer protein.
  24. Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
  25. Amoeboid-Mesenchymal Transition and the Proteolytic Control of Cancer Invasion Plasticity.
  26. Raman-based label-free microscopic analysis of the pancreas in living zebrafish larvae.
  27. Engineering Cancer's Journey: Emerging Tools for Metastasis Modeling.
  28. Targeting of HIF2-driven cachexia in kidney cancer.
  29. Compressed sensing expands the multiplexity of imaging mass cytometry.
  30. Oxytocin treatment reduces cancer cachexia in a pre-clinical model.
  31. Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas: current understanding and perspectives on malignant progression.
  32. Spatially Resolved Ion Sensing by Voltammetric Ion Transfer Microscopy.
  33. Proteomic profiling of extracellular fluids to identify secreted proteins from muscle and fat tissues.
  34. A metabolic atlas of mouse aging.
  1. Nat Commun. 2025 Nov 26. 16(1): 10539
    Adherent cells sustain membrane tension gradients independently of migration.
    Juan Manuel García-Arcos, Amine Mehidi, Julissa Sanchez-Velasquez, Pau Guillamat, Caterina Tomba, Laura Houzet, Laura Capolupo, Javier Espadas, Giovanni D'Angelo, Adai Colom, Elizabeth Hinde, Charlotte Aumeier, Aurélien Roux.
      Tension propagates in lipid bilayers over hundreds of microns within milliseconds, seemingly precluding the formation of tension gradients. Nevertheless, plasma membrane tension gradients have been reported in migrating cells and along growing axons. Here, we show that the mechanosensitive, fluorescent membrane probe Flipper-TR visualizes membrane tension gradients in artificial and cellular membranes. Images of tension gradients allow their quantitative characterization, showing that they are long-ranged and linear in all migratory adherent cells. Using this tool, we unexpectedly reveal that tension gradients also exist in non-migrating adherent cells while they are absent in non-adherent migrating cells. This suggests that actomyosin forces can generate tension gradients even in non-moving cells, but that adhesion to a substrate is needed to sustain these gradients. Treatment of cells with drugs perturbing actomyosin show that branched actin increases tension, creating gradients. Furthermore, specific adhesion mediated by clathrin plaques colocalizes with regions of low tension, and chemical disruption of clathrin plaques strongly affect tension gradients. Altogether, our results show that the combined action of actomyosin and adhesion forces create tension gradients in the plasma membrane of adherent cells, even the ones not migrating.
    DOI:  https://doi.org/10.1038/s41467-025-65571-9
  2. bioRxiv. 2025 Oct 22. pii: 2025.10.21.683287. [Epub ahead of print]
    JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake.
    Ezequiel Dantas, Anirudh Murthy, Jeshua Kim, Tanvir Ahmed, Mujmmail Ahmed, Tiffany Perrier, Shakti Ramsamooj, Isaac Nathoo, Lucas Kniess Debarba, Andre Lima Queiroz, Shiri Li, Baran Ersoy, Miriam Ferrer, Ido Goldstein, Jonathan Gao, Tiffany Lam, Matthew Nagler, Murtaza Malbari, Nasser Altorki, Eduardo Cararo Lopes, Maria Gomez Jenkins, Trishna Das, Mariam Jamal-Hanjani, Eileen White, Tobias Janowitz, Marcus D Goncalves.
      Lung cancer is the leading cause of cancer-related death and is frequently accompanied by reduced food intake and cachexia, a debilitating syndrome characterized by weight loss and skeletal muscle wasting. We sought to identify contributors to cachexia using a murine model of lung cancer that reproduces key features of this syndrome. A multiplex cytokine screening approach, integrated with western blot and transcriptomic analyses, identified tumor-derived inflammatory mediators and downstream signaling pathways associated with cachexia. Notably, IL-6 superfamily members were elevated in the tumor and plasma of mice and patients with cachexia. The JAK-STAT3 signaling was upregulated in liver and skeletal muscle, driving the acute phase response and impairing lipid metabolism. Pharmacologic inhibition of JAK1/2 with ruxolitinib improved body weight, fat mass, and overall survival without altering tumor burden. These effects were driven primarily by blunted hypothalamic leptin receptor signaling, which increased food intake early in the disease course. In the liver, JAK inhibition reduced STAT3 activity, restored fatty acid oxidation, and decreased the production of acute-phase proteins. These findings support JAK inhibition as a therapeutic strategy for lung cancer-associated cachexia.
    DOI:  https://doi.org/10.1101/2025.10.21.683287
  3. Trends Cancer. 2025 Nov 25. pii: S2405-8033(25)00260-2. [Epub ahead of print]
    Interplay between cancer cell lipotypes and disease states.
    Xi Wang, Yilong Zou.
      While the initial transformation of cancer cells is driven by genetic alterations, tumor cell behaviors and functional states are dynamically regulated by cell-intrinsic factors including proteins, metabolites and lipids, and extrinsic microenvironmental factors. Emerging multi-omics technologies highlighted that cancer cells exhibit distinct lipidome compositions and employ specific lipid metabolic circuits for chemical conversions - collectively defined as 'lipotypes'. We review the interplay between cancer lipotypes and cellular states, focusing on interpreting how being at different positions along the spectra of representative lipid metabolic axes influences cancerous traits. We aim to instill a system biology perspective to integrate 'lipotypes' into the established 'genotype-phenotype' framework in cancer.
    Keywords:  cancer progression and metastasis; lipid biosynthesis; lipid metabolism; lipidomics; lipotypes; storage and degradation; tumor microenvironment; uptake
    DOI:  https://doi.org/10.1016/j.trecan.2025.10.009
  4. Cancer Res Commun. 2025 Nov 24.
    MicroCT enables simultaneous longitudinal tracking of murine pancreatic cancer progression and cachexia.
    Katherine R Pelz, Philip Jimenez, Colin J Daniel, Samuel D Newton, Melissa Cunningham, Rosalie C Sears, Patrick J Worth, Jonathan R Brody, Teresa A Zimmers.
      Preclinical models of pancreatic ductal adenocarcinoma (PDAC) can greatly benefit from noninvasive imaging for evaluating disease progression and therapeutic response. Imaging approaches that can accurately and simultaneously track primary tumor growth, metastatic dissemination, and host cachexia over time are lacking. Herein, we report an optimized dual-contrast micro-computed tomography (microCT) protocol for longitudinal imaging in orthotopic murine models of PDAC. This method enables high-resolution, volumetric quantification of orthotopic primary tumors, liver and lung metastases, and paraspinal skeletal muscle, providing a dynamic view of both the tumor and host physiology. MicroCT primary tumor measurements were strongly correlated with endpoint tumor weights and outperformed 2D ultrasound in early detection and volumetric accuracy, particularly for small or irregularly shaped tumors. This platform revealed heterogeneous metastatic kinetics across PDAC models and uncovered an early, heterogeneous onset of skeletal muscle wasting, a hallmark of cancer cachexia. Notably, this protocol mimics clinical CT surveillance by enabling opportunistic cachexia assessment from tumor imaging datasets, and offers substantial advantages over destructive endpoint analyses. Furthermore, microCT radiation dose had no effect on model endpoints. By capturing the temporal dynamics of tumor progression and host response, dual-contrast microCT serves as a powerful translational platform for preclinical PDAC research and therapeutic testing.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0414
  5. bioRxiv. 2025 Nov 04. pii: 2025.11.03.686234. [Epub ahead of print]
    Integrative analysis of genomic and transcriptomic data informs precancer progression in the pancreas.
    Kathleen Noller, Jiaying Lai, Daniel Lesperance, Ricky S Adkins, Ahmed Elhossiny, Paola A Guerrero, Kimal I Rajapakshe, Anirban Maitra, Michelle Giglio, Anup Mahurkar, Owen White, Marina Pasca Di Magliano, Michael F Ochs, Luciane T Kagohara, Laura D Wood, Rachel Karchin, Elana J Fertig.
      Pancreatic ductal adenocarcinoma (PDAC) arises from heterogeneous precursor lesions, including intraductal papillary mucinous neoplasms (IPMNs), but the features distinguishing indolent from progressive lesions remain unclear. We performed an integrative analysis of transcriptomic, genomic, and microenvironmental profiles of IPMNs to define multi-omic phenotypes. Using transfer learning, we projected IPMN-derived transcriptional programs onto spatial transcriptomic datasets from IPMNs and pancreatic intraepithelial neoplasias (PanINs). We identified two major phenotypes: one associated with cancer-associated fibroblasts and epithelial-to-mesenchymal transition, shared across IPMN, PanIN, and PDAC; and a second, glycolysis-enriched phenotype with a unique somatic mutation profile specific to IPMN. Spatial mapping further revealed grade-specific enrichment of transcriptional programs and distinct interactions with stromal and immune subtypes, underscoring the role of the precancer microenvironment in progression. These findings establish multi-omic phenotypes that unify genetic, transcriptional, and microenvironmental heterogeneity, providing a framework for distinguishing progressive from indolent precancers and a web-based public atlas for future exploration of these data and transcriptional phenotypes.
    DOI:  https://doi.org/10.1101/2025.11.03.686234
  6. bioRxiv. 2025 Nov 06. pii: 2025.11.05.686813. [Epub ahead of print]
    Iron addicted colorectal cancers exploit Heme-Complex II axis to resist oxidative cell death.
    Chesta Jain, Muqit Essani, Roshan Kumar, Nupur K Das, Rashi Singhal, Nicholas J Rossiter, Brandon Chen, Wesley Huang, Zheng Hong Lee, Sumeet Solanki, Yuezhong Zhang, Peter Sajjakulnukit, Li Zhang, Prarthana J Dalal, David A Hanna, Shannon McCollum, Elena M Stoffel, Joel K Greenson, L James Maher, Costas A Lyssiotis, Ruma Banerjee, Yatrik M Shah.
      Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and rapid proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most other cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. One pathway thought to mediate iron toxicity is ferroptosis, an iron-dependent form of cell death. However, most ferroptosis regulators were identified through synthetic chemical screens or small molecule activators, and it remains unclear whether these canonical pathways explain how iron itself triggers cell death, particularly in vivo . Here, using multi-omics profiling, CRISPR screening, and in vivo models, we uncover a heme-succinate dehydrogenase (SDH)-Coenzyme Q (CoQ) axis that enables CRC cells to buffer iron-induced oxidative stress. Heme-dependent SDH reduces CoQ, which redistributes to mitochondrial and plasma membranes to detoxify lipid ROS as a radical trapping antioxidant. This pathway functions alongside, and in some contexts independently of, canonical ferroptosis regulators. These findings reveal that CRCs co-opt metabolic cofactors not only for growth but also for survival under physiologically toxic iron levels, uncovering new vulnerabilities for therapy.
    DOI:  https://doi.org/10.1101/2025.11.05.686813
  7. bioRxiv. 2025 Oct 14. pii: 2025.10.13.682232. [Epub ahead of print]
    Homeostatic regulation of intrinsic lipid curvature in eukaryotic cells.
    Daniel Milshteyn, Jacob R Winnikoff, Elida Kocharian, Aaron M Armando, Edward A Dennis, Peter R Girguis, Itay Budin.
      Cell membranes are composed of both bilayer-supporting and non-bilayer phospholipids, with the latter's negative intrinsic curvature aiding in membrane trafficking and the dynamics of membrane proteins. Phospholipid metabolism has long been recognized to maintain membrane fluidity, but whether it also acts to maintain the function of high-curvature lipids is not resolved. Here, we find that cells grown under hydrostatic pressure - used to artificially reduce lipid curvature - maintain lipidome curvature through metabolic acclimation. We first observed that manipulation of the lipidome curvature via the phosphatidylethanolamine (PE) to phosphatidylcholine (PC) ratio affects high-pressure growth and viability of yeast independently of membrane fluidity. In wild-type cells, X-ray scattering measurements revealed an increased propensity for lipid extracts to form non-lamellar phases after extended pressure incubations. Unexpectedly, this change in phase behavior was not due to increased levels of PE, but of phosphatidylinositol (PI), the only major phospholipid class whose curvature had not been previously characterized. We found that PI is a non-bilayer lipid, with a negative curvature intermediate to that of PE and PC. Accounting for PI, mean lipidome curvature was defended in response to pressure by two distantly related yeasts. Lipidome curvature also responded to pressure in a human cancer cell line through ether phospholipid metabolism and chain remodeling, but not in bacterial cells. These findings indicate that eukaryotic phospholipid metabolism uses diverse mechanisms to maintain curvature frustration in cell membranes.
    DOI:  https://doi.org/10.1101/2025.10.13.682232
  8. Curr Opin Biomed Eng. 2025 Dec;pii: 100624. [Epub ahead of print]36
    Fuel, form, and memory: The motility-driven journey of cancer cells.
    Carolina Trenado-Yuste, Celeste M Nelson.
      Tumor progression is a complex, multi-stage process that involves tumor formation, cancer cell invasion, and metastasis and colonization of distant sites. Each stage is driven in part by cell motility and interactions between cancer cells and their surrounding microenvironment. In this review, we describe how cell motility contributes to each stage of cancer progression, with a focus on cell metabolism, nuclear mechanics, and mechanical memory. Throughout, we highlight the mechanisms used by cancer cells to move and adapt during the metastatic cascade. Understanding how cancer cells migrate can provide valuable insights into novel approaches to disrupt metastasis and improve outcomes of cancer treatments.
    Keywords:  Energy metabolism; morphogenesis; tissue morphodynamics
    DOI:  https://doi.org/10.1016/j.cobme.2025.100624
  9. bioRxiv. 2025 Oct 23. pii: 2025.10.23.682519. [Epub ahead of print]
    Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia.
    Takafumi Hara, Gen Tanaka, Tomonori Tamura, Masaomi Terajima, Kengo Hamamura, Yuya Yoshida, Toru Kimura, Yusuke Kasai, Yuta Nakayama, Takumi Umeyama, Kohei Hosoi, Ayaka Noguchi, Yasuno Nakai, Atsushi Hijikata, Koji Matsukawa, Satoru Ujihara, Tetsuhiro Kawabe, Hiroki Taguchi, Hitomi Fujishiro, Supak Jenkitkasemwong, Kazuto Nunomura, Bangzhong Lin, Ayako Fukunaka, Emi Yoshigai, Kenji Mishima, Shinsaku Nakagawa, Michell D Knutson, Hiroshi Imagawa, Naoya Matsunaga, Shigehiro Ohdo, Itaru Hamachi, Hiroyuki Sakurai, Toshiyuki Fukada.
      ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo , PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.
    DOI:  https://doi.org/10.1101/2025.10.23.682519
  10. bioRxiv. 2025 Oct 13. pii: 2025.10.10.681769. [Epub ahead of print]
    Imaging Cellular Metabolic Rewiring with SuMMIT-SRS.
    Yajuan Li, Zhi Li, Yuhan Li, Kevin Rhine, Sural Ranamukhaarachchi, Shuo Qin, Hongje Jang, Jorge Villazon, Zhiliang Bai, Stephanie I Fraley, Gene W Yeo, Rong Fan, Lingyan Shi.
      Cells dynamically rewire their metabolic pathways in response to physiological and pathological cues. Such plasticity is particularly critical in neurons, stem cells, cancer cells, and immune cells, where biosynthetic demands can shift rapidly. However, current metabolic imaging techniques using isotope labeling typically track only one metabolite at a time, limiting their ability to capture the rapid dynamics of complex metabolic networks including coordinated precursor utilization, crosstalk, and turnover. Here, we present Subcellular Multiplexed Metabolic Isotope Tracing Stimulated Raman Scattering microscopy (SuMMIT-SRS), a platform that enables simultaneous visualization of multiple metabolic dynamics at subcellular resolution. By exploiting the distinct vibrational signatures of carbon-deuterium bonds derived from multiple deuterated amino acids, lipids, and monosaccharide tracers, SuMMIT-SRS maps co-regulated DNA, RNA, protein, and lipid synthesis at the same time and resolves various individual amino acid-mediated metabolic pathways within intact cells and tissues. We demonstrate SuMMIT's broad utility across Drosophila fat body tissue and developing brain, tumor organoids, aged human neurons, and mouse liver, capturing cell type-specific metabolic rewiring under genetic and pathological perturbations. This approach extends SRS to multiplexed isotope tracing, offering a powerful tool to uncover dynamic and complex biosynthesis programs in development, health, and disease.
    Keywords:  Metabolic rewiring; SRS; lipid; metabolism; multiplex; optical imaging; protein
    DOI:  https://doi.org/10.1101/2025.10.10.681769
  11. bioRxiv. 2025 Oct 26. pii: 2025.10.25.684524. [Epub ahead of print]
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesize that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility to cell death. We found that large cells are more resistant to ferroptosis induced by system x c - inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides, compared to smaller cells. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the iron-chelating protein ferritin and the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    DOI:  https://doi.org/10.1101/2025.10.25.684524
  12. Cell. 2025 Nov 21. pii: S0092-8674(25)01242-5. [Epub ahead of print]
    Inhibition of oligomeric BAX by an anti-apoptotic dimer.
    Catherine E Newman, Micah A Gygi, Haleh Alimohamadi, Thomas M DeAngelo, Christina M Camara, Julian Mintseris, Ezra Yu, Edward P Harvey, Zachary J Hauseman, Lixin Fan, Yun-Xing Wang, Elizabeth W-C Luo, Marina Godes, Jacob Gehtman, Ann M Cathcart, Steven P Gygi, John R Engen, Gregory H Bird, Gerard C L Wong, Thomas E Wales, Loren D Walensky.
      BAX is a pro-apoptotic BCL-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to form an oligomer that permeabilizes mitochondria and induces apoptosis. The paradigm for apoptotic blockade involves heterodimeric interactions between pro- and anti-apoptotic monomers. Here, we find that full-length BCL-w forms a distinctive, symmetric dimer (BCL-wD) that dissociates oligomeric BAX (BAXO), inhibits mitochondrial translocation, promotes retrotranslocation, blocks membrane-porating activity, and influences apoptosis induction of cells. Structure-function analyses revealed discrete conformational changes upon BCL-w dimerization and reciprocal structural impacts upon BCL-wD and BAXO interaction. Small-angle X-ray scattering (SAXS) analysis demonstrated that BAXO disrupts membranes by inducing negative Gaussian curvature, which is reversed by positive Gaussian curvature exerted by BCL-wD. Systematic truncation and mutagenesis dissected the core features of BCL-wD activity-dimerization, BAXO engagement, and membrane interaction. Our studies reveal a downstream layer of apoptotic control mediated by protein and membrane interactions of higher-order BCL-2 family multimers.
    Keywords:  BAX; BCL-2 family proteins; BCL-w; anti-apoptotic; apoptosis; cell death; chemical crosslinking mass spectrometry; dimer; hydrogen deuterium exchange mass spectrometry; membrane curvature; mitochondria; mitochondrial retrotranslocation; mitochondrial translocation; oligomer; pro-apoptotic; small-angle X-ray scattering
    DOI:  https://doi.org/10.1016/j.cell.2025.10.037
  13. Nat Commun. 2025 Nov 28.
    Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
    Fang Zhou, Robert J Ju, Chenlu Kang, Jiayi Li, Ao Yang, Alexandre Libert, Yujie Sun, Ling Liang, Youwei Ai, Xiaoqing Hu, Samantha J Stehbens, Congying Wu.
      Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death - ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-025-66353-z
  14. Commun Biol. 2025 Nov 24. 8(1): 1645
    Cellular mechanical properties in response to environmental viscosity imaged by Brillouin Microscopy.
    Chenchen Handler, Giulia Zanini, Ian M Smith, Kimberly M Stroka, Giuliano Scarcelli, Claudia Testi.
      An increasing body of research in biomechanics has revealed that the stiffness of the surrounding environment influences cells fate and function. In this context, a recent study showed that cells exposed to highly viscous fluids migrated and spread faster: the viscosity of the surrounding environment thus emerges as a novel potential regulator of key cell functions. To date, however, cellular mechanical responses to this biophysical trigger are widely unconsidered. In this study, we evaluate the mechanical properties of non-cancerous (MCF10A) and highly metastatic cancer (MDA-MB-231) cells grown in fluids of different viscosities by using our custom-built Brillouin Microscope. To achieve this result, we prove that the linewidth of a Brillouin spectrum can serve as a reliable viscosity indicator through an innovative deconvolution method that makes use of a Brillouin Microscope and a Stimulated Brillouin Microscope. Our findings suggest that cancer cells may adapt their internal mechanical properties in response to external media viscosity, thus improving their adaptability to the environment in an active interaction with their surroundings.
    DOI:  https://doi.org/10.1038/s42003-025-09032-5
  15. Cold Spring Harb Perspect Biol. 2025 Nov 24. pii: a041794. [Epub ahead of print]
    Soft Matter Physics Meets Cell Biology: Transitions of Collective Cell Migration in 3D Environments.
    Mirjam M Zegers, Pablo Gottheil, Josef Käs, Peter Friedl.
      Plasticity of cell migration is a hallmark of cell movement during morphogenesis, tissue repair, and cancer metastasis. Interconversions of migration modes are tissue context-dependent and range from (1) collective migration of cohesive cells, migrating as epithelial sheets and strands; (2) multicellular networks of individualized cells moving while maintaining short-lived interactions; and (3) fully individualized cells moving by mesenchymal or amoeboid migration. Modes of cell migration, which are controlled by cell-cell adhesion, cell density, and active forces, can also be represented by physics-derived parameters, including temperature, applied stress, and volume fraction in classical passive jamming phase diagrams. Cell-packing density, cell-cell adhesion strength, and intrinsic migratory capacity have been defined as the key parameters driving jamming transitions in 2D sheet models, where extracellular matrix (ECM) is typically not considered. Here, we review how plasticity of cell migration programs intersects with jamming/unjamming principles and specifically focus on the impact of ECM architectures. In three-dimensional (3D) tissues, additional spatial parameters determine cell density and cell-cell interactions, including the degree of confinement forcing cells together versus the availability of free space. Integrating mechanisms of jamming/unjamming with actin-based active movement of cells in a 3D environment, similar to the motion of active nematic droplets in a passive nematic matrix, will enable building realistic models to predict cell behaviors in physiological and pathological contexts, including cancer metastasis.
    DOI:  https://doi.org/10.1101/cshperspect.a041794
  16. bioRxiv. 2025 Nov 13. pii: 2025.11.11.687895. [Epub ahead of print]
    Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
    Azusa Terasaki, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Keshav Bhatnagar, Cara C Rada, Vishnu Shankar, Courtney Kernick, Mahnoor Mahmood, Lukas Wiggers, Viviana R Rodrigues, Payam A Gammage, Theodore Roth, Jeffrey D Axelrod, Edgar Engleman, Bo Li, Derick Okwan-Duodu.
      Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners.
    HIGHLIGHTS: Tumor cells regulate their ecosystem by redistributing mitochondriaRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cellsMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CSMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem.
    DOI:  https://doi.org/10.1101/2025.11.11.687895
  17. Autophagy. 2025 Nov 28.
    Portioning organelles for autophagic clearance.
    Mikhail Rudinskiy, Maurizio Molinari.
      The lysosomal/vacuolar clearance of portions of organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus and the nucleus, organellophagy, is mediated by autophagy receptors anchored at the surface of their respective organelles. Organellophagy receptors are activated, induced or derepressed in response to stimuli such as nutrient or oxygen deprivation, accumulation of toxic or aged macromolecules, membrane depolarization, pathogen invasion, cell differentiation and many others. Their activation drives the portioning of the homing organelle, and the engagement of Atg8/LC3/GABARAP (LC3) proteins via LC3-interacting regions (LIRs) that results in autophagic clearance. In our latest work, we elaborate on the fact that all known mammalian and yeast organellophagy receptors expose their LIR embedded within intrinsically disordered regions (IDRs), i.e. cytoplasmic stretches of amino acids lacking a fixed three-dimensional structure. Our experiments reveal that the IDR modules of organellophagy receptors are interchangeable, required and sufficient to induce the fragmentation of the organelle that displays them at the limiting membrane, independent of LC3 engagement. LC3 engagement drives lysosomal delivery. Building on these findings, we propose harnessing practical and therapeutic potential of controlled organelle fragmentation and organellophagy through ORGAnelle TArgeting Chimeras (ORGATACs).
    Keywords:  Endoplasmic reticulum (Er)phagy; ORGAnelle TArgeted chimeras (ORGATACs); intrinsically disordered regions (IDRs); mitophagy; organellophagy receptors; targeted organelle degradation
    DOI:  https://doi.org/10.1080/15548627.2025.2597458
  18. Nat Chem Biol. 2025 Nov 28.
    When membrane proteins prefer lipids.
    Edward Lyman.
      
    DOI:  https://doi.org/10.1038/s41589-025-02084-y
  19. Nat Commun. 2025 Nov 28.
    Structural organization of p62 filaments and the cellular ultrastructure of calcium-rich p62-enwrapped lipid droplet cargo.
    Sabrina Berkamp, Lisa Jungbluth, Alexandros Katranidis, Siavash Mostafavi, Olivera Korculanin, Peng-Han Lu, Lotte Ickert, Maya M Dierig, Lokesh Sharma, Lipi Thukral, Pitter F Huesgen, Natalia L Kononenko, Jörg Fitter, Rafal E Dunin-Borkowski, Carsten Sachse.
      The selective autophagy receptor p62/SQSTM1 is known to form higher-order filaments in vitro and to undergo liquid-liquid phase separation when mixed with poly-ubiquitin. Here, we determine the full-length cryo-EM structure of p62 and elucidate a structured double helical filament scaffold composed of the PB1-domain associated with the flexible C-terminal part and the solvent-accessible major groove. At different pH values and upon binding to soluble LC3, LC3-conjugated membranes and poly-ubiquitin, we observe p62 filament re-arrangements in the form of structural unwinding, disassembly, lateral association and bundling, respectively. In the cellular environment, under conditions of ATG5 knockdown leading to stalled autophagy, we imaged high-contrast layers consisting of p62 oligomers enwrapping lipid droplets by cryogenic electron tomography in situ, which we identified as calcium as well as phosphorus by compositional spectroscopy analysis. Together, we visualize the cellular ultrastructure of p62 oligomers with high calcium content as a potential early stage of autophagy.
    DOI:  https://doi.org/10.1038/s41467-025-66785-7
  20. bioRxiv. 2025 Nov 01. pii: 2025.10.31.685804. [Epub ahead of print]
    ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling.
    Joung Hyuck Joo, William Kasberg, Spencer Douglas, Uwemedimo Udoh, Alexandre Carisey, James Messing, Yong-Dong Wang, Shilpa Narina, Shondra M Pruett-Miller, Myriam Labelle, Jennifer Lippincott-Schwartz, Chi-Lun Chang, Mondira Kundu.
      Cancer cells adapt to nutrient stress by remodeling the repertoire of proteins on their surface, enabling survival and progression under starvation conditions. However, the molecular mechanisms by which nutrient cues reshape the cell surface proteome to influence cell behavior remain largely unresolved. Here, we show that acute glucose starvation, but not amino acid deprivation or mTOR inhibition, selectively impairs ER-to-Golgi export of specific cargoes, such as E-cadherin, in a SEC24C-dependent manner. Quantitative cell surface proteomics reveal that glucose deprivation remodels the cell surface proteome, notably reducing surface expression of key adhesion molecules. This nutrient-sensitive reprogramming enhances cell migration in vitro and promotes metastasis in vivo . Mechanistically, we show that AMPK and ULK1 signaling orchestrate this process independent of autophagy, with ULK1-mediated phosphorylation of SEC31A driving SEC24C-dependent COPII reorganization. These findings establish ER-to-Golgi trafficking as a nutrient-sensitive regulatory node that links metabolic stress to cell surface remodeling and metastatic potential.
    DOI:  https://doi.org/10.1101/2025.10.31.685804
  21. Nat Rev Cancer. 2025 Nov 24.
    Targeting macropinocytosis for cancer therapy.
    Daolin Tang, Jiayi Wang, Guido Kroemer, Rui Kang.
      Macropinocytosis is a nutrient-scavenging process that enables cells to engulf large volumes of extracellular fluid and solutes through dynamic plasma membrane ruffling. In cancer, this evolutionarily conserved process is frequently hijacked to meet the heightened metabolic demands of malignant cells, particularly under conditions of nutrient deprivation. Through macropinocytosis, tumour cells internalize diverse extracellular components - including proteins, nucleotides, lipids, ions and debris from dead cells - which are subsequently degraded in lysosomes and recycled to support biosynthesis and energy production. This process is tightly regulated by oncogenic signalling pathways and cues from the tumour microenvironment, including those associated with oncogene activation, loss of tumour suppressors and hypoxia. Beyond facilitating tumour growth and metabolic adaptation, macropinocytosis is implicated in resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy. When excessively activated, it can also lead to methuosis, a form of non-apoptotic cell death characterized by macropinosome overload. This Review outlines the molecular mechanisms and functional consequences of macropinocytosis in cancer, highlighting its dual potential as a metabolic vulnerability and a route for therapeutic delivery. Continued investigation into its regulation, context-specific roles and pharmacological modulation may uncover new opportunities for combination therapies and precision cancer treatment.
    DOI:  https://doi.org/10.1038/s41568-025-00892-x
  22. Mol Cancer. 2025 Nov 28. 24(1): 300
    Downregulation of Sod2 increases atypical flat lesions and dysplasia to advance pancreatic ductal adenocarcinoma.
    Alicia K Fleming Martinez, Heike R Döppler, Ryan Argo, Ligia I Bastea, Brandy H Edenfield, Irene Espositio, Peter Storz.
      
    Keywords:  Initiation; MnSOD; Oxidative stress; PDAC; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s12943-025-02518-0
  23. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2517469122
    ATG2 is a triglyceride transfer protein.
    Justin L Korfhage, Helin Elhan, Neng Wan, Yingying Lu, Lisa Kauffmann, Govindaiah Pilli, Devin M Fuller, Anna M Rios, Karin M Reinisch, Krishna Rao Maddipati, Abdou Rachid Thiam, Thomas J Melia.
      Bridge-like lipid transfer proteins (BLTPs) are established to function in phospholipid transport between bilayers at organelle-organelle contact sites. However, the BLTP ATG2A also associates with lipid droplets in cells, which present a unique phospholipid monolayer topology and which are composed of many additional types of lipids. Whether BLTPs are active in this environment and which lipid species are substrates for transport has been unknown. Here, we use synthetic organelles with bilayers (liposomes), monolayers (artificial lipid droplets), or a mixture of the two membrane structures to demonstrate the tight binding of ATG2 specifically to monolayers via its collection of COOH-terminal amphipathic helices. This stable binding enables ATG2 to transfer phospholipids much more effectively. Unexpectedly, the neutral lipid triacylglycerol is also rapidly transported, with kinetics similar to those of phospholipid transport. Lipidomics of purified ATG2A suggests that a similar transfer of both phospholipids and triacylglycerol occurs in cells. Our work implies that BLTPs likely collect on LDs as part of a broad lipid homeostasis program, which will include the movement of both phospholipids and neutral lipids.
    Keywords:  ATG2A; bridge-like lipid transfer; lipid droplet
    DOI:  https://doi.org/10.1073/pnas.2517469122
  24. bioRxiv. 2025 Oct 23. pii: 2025.10.22.684010. [Epub ahead of print]
    Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
    Wen-Hsuan Yang, Olivia T Stamatatos, Evdokia Michalopoulou, Ava Sann, Paolo Cifani, Linda Van Aelst, Justin R Cross, Tse-Luen Wee, Michael J Lukey.
      Avid nutrient consumption is a metabolic hallmark of cancer and leads to regional depletion of key metabolites within the tumor microenvironment (TME). Cancer cells consequently employ diverse strategies to acquire the fuels needed for growth, including bulk uptake of the extracellular medium by macropinocytosis. Here, we show that breast and pancreatic cancer cells macropinocytically internalize extracellular DNA (exDNA), an abundant component of the TME, and deliver it to lysosomes for degradation. This provides a supply of nucleotides that sustains growth when de novo biosynthesis is impaired by glutamine restriction or pharmacological blockade. Mechanistically, this process is dependent on the non-redundant lysosomal equilibrative nucleoside transporter SLC29A3 (ENT3), which mediates the export of nucleosides from the lysosomal lumen into the cytosol. Accordingly, genetic ablation of SLC29A3 or pharmacological disruption of lysosomal function prevents exDNA scavenging and potently sensitizes breast tumors to antimetabolite chemotherapy in vivo . These findings reveal a previously unrecognized nutrient acquisition pathway through which cancer cells recycle exDNA into metabolic building blocks and highlight SLC29A3 as a mediator of metabolic flexibility and a potential target to improve chemotherapy response.
    DOI:  https://doi.org/10.1101/2025.10.22.684010
  25. bioRxiv. 2025 Oct 24. pii: 2025.10.24.684403. [Epub ahead of print]
    Amoeboid-Mesenchymal Transition and the Proteolytic Control of Cancer Invasion Plasticity.
    Adam W Olson, Jonathan Li, Xiao-Yan Li, Lana King, Kalins Banerjee, Atticus J McCoy, Mahnoor N Gondal, Arul M Chinnaiyan, Dorraya El-Ashry, Evan T Keller, Andrew J Putnam, Stephen J Weiss.
      Invasion plasticity allows malignant cells to toggle between collective, mesenchymal and amoeboid phenotypes while traversing extracellular matrix (ECM) barriers. Current dogma holds that collective and mesenchymal invasion programs trigger the mobilization of proteinases that digest structural barriers dominated by type I collagen, while amoeboid activity allows cancer cells to marshal mechanical forces to traverse tissues independently of ECM proteolysis. Here, we use cancer spheroid-3-dimensional matrix models, single-cell RNA sequencing, and human tissue explants to identify the mechanisms controlling mesenchymal versus amoeboid invasion. Unexpectedly, collective/mesenchymal- and amoeboid-type invasion programs - though distinct - are each characterized by active tunneling through ECM barriers, with expression of matrix-degradative metalloproteinases. CRISPR/Cas9-mediated targeting of a single membrane-anchored collagenase, MMP14/MT1-MMP, ablates tissue-invasive activity while co-regulating cancer cell transcriptional programs. Though changes in matrix architecture, nuclear rigidity, and metabolic stress as well as the presence of cancer-associated fibroblasts are proposed to support amoeboid activity, none of these changes restore invasive activity of MMP14-targeted cancer cells. While a requirement for MMP14 is bypassed in low-density collagen hydrogels, invasion by the proteinase-deleted cells is associated with nuclear envelope and DNA damage, highlighting a proteolytic requirement for maintaining nuclear integrity. Nevertheless, when cancer cells confront explants of live human breast tissue, MMP14 is again required to support invasive activity. Corroborating these results, spatial transcriptomic and immunohistological analyses of invasive human breast cancers identified clear expression of MMP14 in invasive cells that were further associated with degraded collagen, underlining the pathophysiologic importance of this proteinase in directing invasive activity in vivo .
    DOI:  https://doi.org/10.1101/2025.10.24.684403
  26. FEBS Open Bio. 2025 Nov 25.
    Raman-based label-free microscopic analysis of the pancreas in living zebrafish larvae.
    Noura Faraj, Eline M F de Lange, Klaas A Sjollema, Ben N G Giepmans.
      Advanced microscopy techniques, combined with a diverse set of fluorescent probes, provide valuable tools for uncovering insights into biological systems and addressing fundamental research questions. However, the need to develop and use genetic tags and probe markers presents notable challenges. Coherent Raman scattering microscopy offers a label-free alternative, enabling live-cell imaging of cellular structures without the need for labeling. Leveraging the benefits of Raman microscopy, we aim to analyze the pancreas in living zebrafish larvae and to evaluate chemical changes in pancreatic exocrine and endocrine compartments following exocrine damage. Here, we present a protocol for Raman-based label-free microscopic analysis of the pancreas in living zebrafish larvae. Using forward stimulated Raman scattering (F-SRS) and epi coherent anti-Stokes Raman scattering (E-CARS), zebrafish pancreatic structures were analyzed and validated. Vibrational Raman spectra between 450 and 3100 cm-1 were acquired to identify chemical structural features within pancreatic regions. Raman imaging allows discrimination of distinct structures at 2850 and 2934 cm-1 in pancreatic exocrine and endocrine regions, which could mainly correspond to lipids and proteins, respectively. Exocrine damage causes a significant reduction in both the number and size of exocrine granules. Moreover, changes at 2934 cm-1 suggested chemical alterations in both exocrine and beta-cell regions. In conclusion, SRS and CARS provide a powerful, label-free approach for live-cell imaging and chemical analysis in islet biology. Given the relative straightforward applicability in the pancreas, we anticipate broad implementation of Raman microscopy in other organs and across various biomedical research fields.
    Keywords:  E‐CARS; F‐SRS; live‐cell imaging; living zebrafish; pancreas
    DOI:  https://doi.org/10.1002/2211-5463.70163
  27. Curr Opin Biomed Eng. 2025 Nov 15. pii: 100631. [Epub ahead of print]
    Engineering Cancer's Journey: Emerging Tools for Metastasis Modeling.
    Tianna Edwards, Haylee Wagner, Shelly Peyton.
      The overwhelming majority of cancer-associated deaths occur due to metastasis-the spread of cells from the primary tumor to distant organs-where disseminated cells eventually colonize and destroy organ function. For metastasis to occur, a cell must acquire diverse traits, including the ability to migrate away from the primary tumor, cross an endothelial barrier, survive in circulation, re-emerge across a new endothelial barrier at a distant tissue site, and ultimately resume proliferation to colonize a foreign tissue environment. Bioengineers have recognized that tools originally developed for tissue engineering are useful for experimentally modeling cancer and metastasis. Cancer bioengineering is an emerging subfield of biomedical engineering that unifies engineering and cancer biology to better understand, diagnose, and treat cancer. The National Cancer Institute has made a bold call emphasizing the need for these bioengineered in vitro models of cancer to supplement animal models. Hypothesis testing, large discovery-based screens, and mechanistic studies of metastasis in in vitro models may help guide ensuing, targeted animal studies. In this brief, forward looking review, we discuss whether and how in vitro models can be used to study the full metastatic cascade, from invasion to outgrowth, and what must continue to be developed so that the models faithfully recapitulate the full disease progression and are approachable for scientists worldwide.
    Keywords:  cancer bioengineering; in vitro model; metastatic cascade
    DOI:  https://doi.org/10.1016/j.cobme.2025.100631
  28. Nat Med. 2025 Nov 28.
    Targeting of HIF2-driven cachexia in kidney cancer.
    Muhannad Abu-Remaileh, Laura A Stransky, Nikita Bhalerao, Nitin H Shirole, Qinqin Jiang, Eddy Saad, Marc Machaalani, Sean M Vigeant, Hilina Woldemichael, Charles Xu, Jing Lu, Hairong Wei, Zhihong Liu, William Sun, Kei Enomoto, Toni K Choueiri, Jason R Pitarresi, Steven A Carr, Namrata D Udeshi, William G Kaelin.
      Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC), is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in patients with ccRCC, including in some who did not exhibit objective tumor shrinkage. Our findings support prospective clinical studies to determine whether HIF2 inhibitors can be leveraged not only for tumor control, but also for the treatment of cancer-associated cachexia in renal cell carcinoma.
    DOI:  https://doi.org/10.1038/s41591-025-04054-2
  29. Nat Commun. 2025 Nov 27.
    Compressed sensing expands the multiplexity of imaging mass cytometry.
    Tsuyoshi Hosogane, Leonor Schubert Santana, Nils Eling, Holger Moch, Bernd Bodenmiller.
      The multiplexity of current antibody-based imaging is limited by the number of reporters that can be detected simultaneously. Compressed sensing can be used to reconstruct high-dimensional information from low-dimensional measurements. Previously, compressed sensing using composite in situ imaging (CISI) of transcriptomic data leveraged gene co-regulation structure to recover spatial expression of 37 RNA species from images of 11 composite channels. Here, we extend the CISI framework to protein expression data measured by imaging mass cytometry (IMC). CISI-IMC accurately recovers spatial expression of 16 immune and stromal marker proteins from images of 8 composite channels with an average Pearson's correlation of 0.8 across protein. Training the CISI-IMC framework using data collected on multiple human tissues enables universal decompression of composite data from a wide range of tumor and healthy tissue types. The expression dictionary and barcoding matrix described here are immediately implementable for general immune and stromal cell type classification, but CISI-IMC can in principle be applied to other markers or other antibody-based imaging methods. Our work lays the foundation for much higher plex protein imaging.
    DOI:  https://doi.org/10.1038/s41467-025-66629-4
  30. Biomed Pharmacother. 2025 Nov 25. pii: S0753-3322(25)01019-4. [Epub ahead of print]193 118825
    Oxytocin treatment reduces cancer cachexia in a pre-clinical model.
    Alexandra Sviercovich, Etsuko Watanabe, Estefania S Fernandez, Alessandra Renzini, Chao Liu, Grace Xie, Jasmine Cao, Zhenlin Li, Onnik Agbulut, Marilia Seelaender, Jose Pinhata Otoch, Daniele De Meo, Gianluca Cera, Viviana Moresi, Francesca Palermo, Sergio Adamo, Michael J Conboy, Irina M Conboy, Dario Coletti.
      Oxytocin (OT) is a neurohypophyseal peptide with decreased expression during aging, essential for skeletal muscle homeostasis, and counteracts sarcopenia in aged mice. Yet, its function in cancer cachexia remains unexplored. We investigated OT serum levels in cancer patients, comparing these with cachectic patients and non-cancer controls, as well as OT/OT-receptor (OTR) mRNA in sarcopenic muscle. Potential benefits of OT were assessed in vitro using L6C5 myoblasts and murine isolated myofibers exposed to C26-conditioned medium and in vivo using the C26/Balb/c cancer cachexia model. Finally, the molecular effects of OT on de novo protein synthesis via bio-orthogonal non-canonical amino acid tagging (BONCAT) were investigated using MetRSL274G C57BL/6 mice. Circulating OT was significantly lower in cancer patients than in non-cancer disease (-60 %, p < 0.01). Sarcopenic muscle showed over threefold downregulation of the OTR (p < 0.032). In vitro, OT reversed the myogenic inhibition induced by tumor cell-conditioned medium, boosting fusion index (>6-fold, p < 0.001), nuclei per myotube (>8-fold, p < 0.001), and myotube diameter (>6-fold, p < 0.001). In C26 tumor-bearing mice, OT restored skeletal muscle mass (>1.5-fold, p < 0.001), fiber cross-sectional area (>1.5-fold, p < 0.001), and overall body weight, while reducing the muscle degradation determinants: MuRF1 (>8-fold, p < 0.001) and Atrogin1 (>6-fold, p < 0.001). Metabolic proteomics showed that cancer perturbed and OT restored the synthesis of key proteins (+23 %, p < 0.05) that play essential roles in muscle regeneration and inter-organ communication. Given that OT is approved for clinical use, our findings suggest that it could quickly be translated into effective therapies for preventing or treating cachexia in cancer patients.
    Keywords:  BONCAT; Cancer cachexia; Oxytocin; Protein metabolism
    DOI:  https://doi.org/10.1016/j.biopha.2025.118825
  31. J Gastroenterol. 2025 Nov 26.
    Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas: current understanding and perspectives on malignant progression.
    Yuki Makino, Kohki Oyama, Akiko Sagara, Fredrik Ivar Thege, Anirban Maitra.
      Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC), which is the cancer type with the most dismal prognosis. Since IPMNs are detectable by imaging, they offer a rare window of opportunity for early intervention for PDAC development. Despite their clinical visibility, the molecular pathogenesis of IPMNs remained incompletely understood, and no effective non-surgical therapeutic strategies have been established to date. In the past few decades, however, substantial progress has been made in elucidating their molecular pathology. Next-generation sequencing technologies demonstrated the comprehensive genetic mutation profile of IPMNs in the early 2010s. Elucidation of these mutation profiles enabled the establishment of genetically engineered mouse models, successfully recapitulating the natural development of human IPMNs and their progression to invasive cancer. Rapid evolution of "omics" technologies in recent years has facilitated the application of mass spectrometry, single-cell sequencing and spatial transcriptomics to IPMNs, significantly advancing our understanding of their pathophysiology. These techniques elucidated the changes in transcriptome, proteome, metabolome, microbiome, and tumor microenvironment associated with IPMN development and progression. This review summarizes current insights into the molecular and cellular landscapes of IPMN tumorigenesis, with particular emphasis on the mechanisms driving malignant progression.
    Keywords:  IPMN; Molecular pathology; Multi-omics; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s00535-025-02328-7
  32. JACS Au. 2025 Nov 24. 5(11): 5538-5546
    Spatially Resolved Ion Sensing by Voltammetric Ion Transfer Microscopy.
    Gabriel J Mattos, Justine A Rothen, Thomas J Cherubini, Eric Bakker.
      The visualization and mapping of ionic species in solution and near surfaces are important to understand chemical gradients and spatially resolved dynamic processes in various fields. Available label-free approaches are either slow or restricted to a few parameters, such as pH. We introduce here a novel chemical mapping principle for the spatially resolved sensing of optically silent ionic species at high frequency, acquiring a concentration map of millions of pixels in seconds using a conventional fluorescence microscope. The principle relies on ion transfer from a thin polymeric film into a solution phase, electrochemically coupled to electron transfer at the back side of the film. Different solution concentrations change the potential at which ion transfer is observed, which is visualized by unquenching a fluorophore when the redox probe in the film is electrochemically oxidized. The moment of maximum fluorescence change for each pixel is captured by a rapid image burst to simultaneously find the excitation peak potentials for all pixels. This produces a concentration map, turning a single sensing film into a chemical imaging platform that provides millions of concentration points. The imaging principle is demonstrated with a flowing junction to map diffusional mixing of two solution streams with different ion concentrations, using tetraethylammonium as an initial model ion, to achieve micrometer spatial resolution.
    Keywords:  Electrochemical imaging; Fluorescence; Ion-selective membrane; Quantitative mapping; TEMPO
    DOI:  https://doi.org/10.1021/jacsau.5c01034
  33. Methods Cell Biol. 2026 ;pii: S0091-679X(24)00187-0. [Epub ahead of print]200 171-195
    Proteomic profiling of extracellular fluids to identify secreted proteins from muscle and fat tissues.
    Melanie J Mittenbühler, Amanda L Smythers, Bruce M Spiegelman.
      Communication between tissues or different cells within a tissue is often a result of secreted molecules such as metabolites, lipids, nucleic acids, or proteins (referred to as the secretome). These enter the extracellular space and may subsequently pass into the circulation. Depending on their nature, concentration and context, these molecules initiate specific responses in their target cells. Environmental stimuli such as exercise and cold exposure, but also different diseases, are known to significantly alter the secretome and thereby affect whole body homeostasis. Thus, identifying these factors is of great interest. The analysis of secreted proteins, however, represents a unique challenge for the field. This is mainly because mass spectrometry can be limited by the dynamic range problem, whereby the detection of low abundance polypeptides can be masked by the presence of high abundance proteins. Plasma, muscle, and fat all contain specific proteins of very high abundance, making it tremendously challenging to detect low abundance proteins in these biological samples. Thus, secreted, hormone-like polypeptides frequently remain undetected. Because muscle and fat are known to communicate by secretion of myokines and adipokines, respectively, we have sought to develop methods that can circumvent these issues through the isolation of extracellular fluids (EF) which surround these tissues. EFs had previously been isolated for analysis of metabolites; however, whether this method could be made useful for in depth proteomics analysis was not known. Recently, we have developed a method that modifies these procedures and makes it applicable for the study of EF proteins. We have applied this to muscle and fat EFs, but in principle, it can be used to study secreted proteins from almost any tissue in any species, including humans. A step-by-step protocol and methods of quality control are given below.
    Keywords:  Extracellular fluid proteomics; Secreted proteins; Secretome; Secretomics
    DOI:  https://doi.org/10.1016/bs.mcb.2024.08.004
  34. Cell Metab. 2025 Nov 25. pii: S1550-4131(25)00476-0. [Epub ahead of print]
    A metabolic atlas of mouse aging.
    Steven E Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H Lee, Ernst Schmid, Ipsita Mohanty, Jenna L E Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison K A Wong, Yaqi Gao, George Wang, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Anja Karlstaedt, Timothy L Frankel, Marina Pasca di Magliano, Whitaker Cohn, Sophia Liu, Bingfei Yu, Pieter C Dorrestein, Ernest Fraenkel, Shawn M Davidson, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.
      Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.
    Keywords:  LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.016
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