bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–04–19
forty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
  2. Altered PI3K and ERK/MAPK Signaling in KRASG12R-Driven Pancreatic Cancer Presents Opportunities for Precision Therapy.
  3. Cell death in cancer.
  4. Measurement of plasma membrane rupture via confocal microscopy.
  5. SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
  6. Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.
  7. Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress.
  8. Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.
  9. Regulatory elements in the Sox9 locus license the initiation of pancreatic ductal adenocarcinoma.
  10. CA19-9 promotes liver metastasis of pancreatic cancer through E-selectin mediated extravasation.
  11. Membrane Curvature and Cancer: Mechanisms, Implications, and Therapeutic Perspectives.
  12. Large-scale endoplasmic reticulum membrane solidification spatially organizes proteins under thermal or metabolic stress.
  13. Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.
  14. Phase-field approach to cellular blebbing.
  15. Super resolution microscopy-based assessment of organellar redox-active iron transfer and its relevance for ferroptosis.
  16. Aging changes cell mechanics and dynamics associated with cytoplasmic crowding.
  17. Tumour promotion through the lens of evolution.
  18. Cancer neuroscience: The past, the present, and the road ahead.
  19. Fine-Tuning Autophagy in Skeletal Muscle: From Homeostasis to Muscle Wasting Disorders.
  20. TAX1BP1 targets STING1 via microautophagy and Golgiphagy to limit inflammatory signaling.
  21. 4D whole-cell model of a minimal cell.
  22. Membrane Binding and Pro-Ferroptotic Activity of NQO1.
  23. Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial.
  24. Controlling tissue size by active fracture.
  25. Txnrd2 loss in skeletal muscle causes muscle atrophy and drives leanness and obesity resistance.
  26. Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance.
  27. pH gradient-driven deformation of a crista-like vesicle.
  28. Appeals: what, why, when, how.
  29. Hallmarks of cancer research: Enabling transformative discovery through global team science.
  30. Mapping intratumor heterogeneity across layers for advancing immunotherapy.
  31. Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
  32. Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
  33. Tackling the complexity of cancer with generative models.
  34. Training the Next Generation of AI-Enabled Cancer Scientists.
  35. An isoform of 14-3-3 protein regulates transbilayer lipid movement at the plasma membrane.
  36. Bacterial protein-oleate complexes induce ferroptosis-like cell death in colorectal cancer cells by disrupting cell membranes and inhibiting the β-catenin-GPX4 axis.
  37. Establishing whole-body cellomics.
  38. Lipid-trap mass spectrometry identifies lipid-protein interactions in cells.
  39. Implementation of the FENIX assay to assess the anti-ferroptotic properties of test compounds.
  40. FDA approves wearable device for pancreatic cancer.
  1. Cell. 2026 Apr 15. pii: S0092-8674(26)00333-8. [Epub ahead of print]
    Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition.
    José Reyes, Isabella Del Priore, Andrea C Chaikovsky, Nikhita Pasnuri, Ahmed M Elhossiny, Jin Park, Philipp Weiler, Tobias Krause, Andrew Moorman, Catherine Snopkowski, Meril Takizawa, Cassandra Burdziak, Nalin Ratnayeke, Ignas Masilionis, Yu-Jui Ho, Ronan Chaligné, Paul B Romesser, Aveline Filliol, Tal Nawy, John P Morris, Zhen Zhao, Marina Pasca Di Magliano, Direna Alonso-Curbelo, Dana Pe'er, Scott W Lowe.
      The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.
    Keywords:  KRAS inhibitors; benign-to-malignant transition; niche dynamics; p53; pancreatic cancer; single-cell biology; spatial transcriptomics; tumor initiation; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.03.032
  2. Cancer Res. 2026 Apr 15. 86(8): 1817-1819
    Altered PI3K and ERK/MAPK Signaling in KRASG12R-Driven Pancreatic Cancer Presents Opportunities for Precision Therapy.
    Hervé Tiriac, Dannielle D Engle.
      Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies with near-universal KRAS mutation. Although KRASG12D and KRASG12V are predominant, KRASG12R is also prevalent in PDAC yet rare in other KRAS-driven cancers such as lung and colorectal adenocarcinoma, suggesting pancreas-specific selective pressures. Unlike other KRAS mutants, KRASG12R fails to productively engage key nodes that amplify oncogenic output including wild-type (WT) RAS and PI3K signaling. Furthermore, KRASG12R-mutant PDAC has been shown to be more sensitive to MAPK/ERK inhibition compared with other KRAS-mutant tumors. Three complementary studies now clarify how KRASG12R promotes PDAC growth and why this genotype may carry distinct therapeutic vulnerabilities. First, Burge and colleagues identify KRASG12R-independent PI3K maintenance driven by PTEN oxidation and broad PI3K isoform utilization, with nutrient limitation further enhancing PTEN oxidation. Second, in a separate study, Burge and colleagues develop KRASG12R mouse models and show that KRASG12R tumors exhibit reduced ERK/MAPK transcription, collagen deposition, and metastasis. Third, Kamgar and colleagues demonstrate an impaired cross-talk of KRASG12R with WT RAS and stoichiometric dependencies that help explain heightened MEK inhibitor sensitivity, supported by clinical trials combining MEK and autophagy inhibition. Together, these articles reposition KRASG12R PDAC as a biologically constrained yet therapeutically exploitable subtype. See related article by Burge et al., p. 1854 See related article by Burge et al., p. 1868 See related article by Kamgar et al., p. 2042.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5676
  3. Cell. 2026 Apr 16. pii: S0092-8674(26)00325-9. [Epub ahead of print]189(8): 2322-2356
    Cell death in cancer.
    Marcus Conrad, Andreas Strasser, Philipp J Jost, Junying Yuan, Feng Shao, Peter Vandenabeele, Adam Wahida.
      "Evasion of cell death" is a hallmark of cancer, enabling transformed cells to withstand oncogenic and therapeutic stress. Restoring cancer cell death is an appealing strategy but requires a deep understanding of cell death programs. Over the past two decades, the cell death field has expanded from apoptosis to include necroptosis, pyroptosis, ferroptosis, and other emerging programs, reshaping cancer biology and revealing therapeutic opportunities. While apoptosis remains the primary radiation- and chemotherapy-induced cell death program, non-apoptotic programs can drive inflammatory responses and orchestrate the interplay among tumor, stroma, and immune components, influencing immunotherapy outcomes. Ferroptosis, an iron-dependent, lipid peroxidation-driven cell death modality, lacks a canonical induction signal and arises from perturbations in lipid, iron, and redox metabolism. This review presents a unified framework for understanding the roles of major cell death programs in cancer development, progression, and treatment response, as well as addressing resistance to cancer cell death and immune suppression. "Our bodies are made of cells that live, and just as surely, of cells that must die." -S. Brenner.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.024
  4. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00010-5. [Epub ahead of print]205 47-62
    Measurement of plasma membrane rupture via confocal microscopy.
    Laurel B Stine, Fiachra Humphries.
      To maintain homeostasis, cells undergo a tightly regulated process called programmed cell death. Some forms of programmed cell death, such as pyroptosis, can elicit a strong inflammatory response by releasing cytokines through small protein pores. The terminal event of pyroptosis in most cells is plasma membrane rupture (PMR), which breaks down large sections of the plasma membrane and emits intracellular contents that can further amplify the inflammatory signal. In opposition to the previous dogma that PMR is a passive event, it was recently discovered that the transmembrane protein, Ninjurin-1 (NINJ1), is the key executor of PMR. Two models of NINJ1-mediated PMR predict that NINJ1 oligomerizes into filaments or ring-like structures to either open large pores or to excise sections of the membrane. Both models underpin how NINJ1 must oligomerize to execute PMR. When at rest, NINJ1 will autoinhibit oligomerization and activation by forming face-to-face dimer-dimer structures on the plasma membrane. Follow-up studies have shown that NINJ1 executes PMR for other forms of programmed cell death, including apoptosis, ferroptosis, and PANoptosis, as well as mechanical cell death. Thus, assessing NINJ1 function directly through quantification of NINJ1 oligomerization is important to expanding our understanding of both programmed and mechanistic cell death. Here, we describe methods to visualize and quantify NINJ1 oligomerization via immunofluorescence imaging of NINJ1 puncta. This protocol enables more precise and accurate measurement of NINJ1 function during PMR, surpassing conventional methods that just quantify PMR by-products.
    Keywords:  Cell death; Inflammasome; Ninjurin1; Plasma membrane rupture; Pyroptosis
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.010
  5. Nat Cell Biol. 2026 Apr 17.
    SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
    Shanshan Liu, Mark Gad, Caifan Li, Kevin Cho, Yuyang Liu, Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J Patti, Ekaterina V Vinogradova, Richard K Hite, Kıvanç Birsoy.
      The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 led to GSSG accumulation in the ER and a liposome-based assay demonstrated that SLC33A1 directly transports GSSG. Cryogenic electron microscopy structures and molecular dynamics simulations revealed how SLC33A1 binds GSSG and identified residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induced ER stress and dependency on the ER-associated degradation pathway, driven by a shift in protein disulfide isomerases towards their oxidized forms. Together, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.
    DOI:  https://doi.org/10.1038/s41556-026-01922-y
  6. Cancer Cell. 2026 Apr 16. pii: S1535-6108(26)00166-2. [Epub ahead of print]
    Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.
    Yuqing Zhang, Ryan D Nipp, Tobias Janowitz, Yi-Ping Li, Denis C Guttridge, Min Li.
      Cancer cachexia is a systemic metabolic syndrome driven by tumor-induced disruption of whole-body homeostasis. Characterized by skeletal muscle atrophy and adipose tissue loss, cachexia leads to functional decline, impaired quality of life, reduced treatment tolerance, and poor survival across multiple malignancies. Emerging evidence indicates that cachexia arises from complex and dynamic interactions between tumors and host organ systems, including immune, metabolic, endocrine, and neural networks, that collectively reshape energy balance, immune function, and tissue integrity. Despite its profound clinical impact, effective therapies remain limited, reflecting incomplete mechanistic understanding and the absence of integrated clinical frameworks. Here, we review recent advances in cachexia biology, including tumor-host signaling, multiorgan metabolic remodeling, and neuroendocrine regulation. We further propose a tumor-centric framework in which cachexia represents a progressive collapse of systemic homeostasis and outline translational strategies to guide mechanism-informed therapeutic interventions.
    Keywords:  adipose tissue loss; anorexia; cancer cachexia; energy balance; metabolic reprogramming; neuroendocrine regulation; skeletal muscle wasting; systemic inflammation; tumor-host interactions; whole-body homeostasis
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.012
  7. Cell Chem Biol. 2026 Apr 13. pii: S2451-9456(26)00074-7. [Epub ahead of print]
    Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress.
    Alex E Ekvik, Megan M Kober, Denis V Titov.
      The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to alterations in the energy state by sensing changes in the ratio of ATP, ADP, AMP, and inorganic phosphate levels. A key barrier to understanding how this happens is a lack of tools for direct manipulation of the energy state in living cells. Here, we introduce ATPGobble-a genetically encoded tool that hydrolyzes ATP in vivo. ATPGobble increases the metabolic rate, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK in human cells. We performed a systematic analysis of proteome and phosphoproteome changes caused by ATPGobble, and found that it remodels cytoskeleton, cell cycle, and translation machinery. Our results establish ATPGobble as a powerful new tool for dissecting the regulatory roles of energy state in living cells.
    Keywords:  AMPK; ATP; ATP/ADP ratio; F1 ATPase; cell fitness; energy status; energy stress; genetically encoded tools; phosphoproteomics; proteomics
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.004
  8. Nat Commun. 2026 Apr 15.
    Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.
    Verena Wagner, Laura Bousset, Mariana Ascensão-Ferreira, Bin Sun, José Efren Barragan Avila, Alexandre Kaizeler, Rita Martins-Silva, Mohammad Rahbari, Mirian Fernández-Vaquero, Scott Haston, Michele Tinti, Joaquim Pombo, Sanjay Khadayate, Susanne Roth, Christian M Schürch, Juan Pedro Martínez-Barbera, Anat Bahat, Keng Boon Wee, Jennifer P Morton, Nisar Malek, Andrew J Innes, Santiago Vernia, Nuno L Barbosa-Morais, Suchira Gallage, Mathias Heikenwalder, Jesús Gil.
      RAS family proteins, including HRAS, NRAS, and KRAS, are frequently mutated in cancer. Although there has been recent success in designing inhibitors that target oncogenic RAS, they elicit resistance and treating RAS-driven cancer remains difficult. Here, employing a proteomic analysis, we find that multiple spliceosome components are upregulated in the nuclei of cells undergoing RAS-induced senescence. This upregulation depends on RAS signalling and occurs in both senescent preneoplastic and fully transformed cancer cells. Spliceosome components are also highly expressed in preneoplastic and cancerous lesions in human and murine lung, liver, colorectal, and pancreatic cancers. Using siRNA screens, we identify six spliceosome components, including SF3B1 and RBM39, that are essential in cells expressing oncogenic RAS. We find that SF3B1 is required in these cells for maintaining splicing fidelity. By combining transcriptome and splicing analyses with functional screens, we identify the RNA Pol II-associated factor SPT5 as a key mediator of the SF3B1 effects. Importantly, using mouse models of liver cancer, we show that RBM39 and SF3B1 inhibitors are effective in targeting both preneoplastic lesions and aggressive tumours expressing oncogenic RAS. In summary, our study highlights the spliceosome as a promising target for RAS-driven cancers capable of inhibiting both cancer initiation and progression.
    DOI:  https://doi.org/10.1038/s41467-026-71564-z
  9. Cell Rep. 2026 Apr 13. pii: S2211-1247(26)00254-8. [Epub ahead of print]45(4): 117176
    Regulatory elements in the Sox9 locus license the initiation of pancreatic ductal adenocarcinoma.
    Marta Ballester, Anita Kurilla, Yifan Dai, Leire Bergara-Muguruza, Katarzyna Radke, H Carlo Maurer, Elisa Espinet, Kristina Høj, Aida Marisch-Delgado, Philip A Seymour, Saynab Omar, Charlotte Vestrup Rift, Jane Hasselby, Pia Klausen, Peter Vilmann, Ainara Castellanos-Rubio, Izortze Santin, Albin Sandelin, Luis Arnes.
      Cellular plasticity enables tissue regeneration but can be hijacked by oncogenic programs. In the pancreas, Kras acts on tissue-specific enhancers to lock regeneration into a pro-inflammatory state that drives cancer initiation. Enhancer transcription, an early event during cell state transitions, generates long noncoding RNAs (lncRNAs) that influence transcription and genome organization, yet their roles in pancreatic regeneration remain unclear. We profiled epithelial lncRNAs and their targets during pancreatic ductal adenocarcinoma (PDAC) precursor formation, focusing on those transcribed from enhancers near cell identity regulators. LINC00673, expressed from a Sox9-associated super-enhancer during development, is reactivated in PDAC. Conditional deletion of LINC00673 accelerates acinar-to-ductal metaplasia resolution and impairs PDAC initiation. Moreover, LINC00673 harbors a variant associated with PDAC risk. In addition, our data are consistent with a contribution of transcribed super-enhancers to long-range gene regulation during pancreatic cancer initiation. These findings reveal a regulatory layer linking developmental enhancer activity, cellular plasticity, and pancreatic disease progression.
    Keywords:  3D genome organization; CP: cancer; CP: developmental biology; Kras; Sox9; acinar-to-ductal metaplasia; pancreatic cancer; pancreatic development; pancreatic intraepithelial neoplasia; pancreatic regeneration; pancreatitis; super-enhancers
    DOI:  https://doi.org/10.1016/j.celrep.2026.117176
  10. bioRxiv. 2026 Apr 10. pii: 2026.04.08.717301. [Epub ahead of print]
    CA19-9 promotes liver metastasis of pancreatic cancer through E-selectin mediated extravasation.
    Satoshi Ogawa, Hyemin Song, Jasper Hsu, Vasiliki Pantazopoulou, Victoria Osorio-Vasquez, Casie S Kubota, Jacob R Tremblay, Chelsea R Bottomley, Kathryn Lande, Jonathan Zhu, Kristina L Peck, Yongjia Wang, Kassidy Curtis, Sophie Keightley, Ryan Tomita, Jingjing Zou, Michael Downes, Ronald M Evans, Andrew M Lowy, Herve Tiriac, Dannielle D Engle.
      Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, which drives patient mortality. CA19-9 is elevated in most PDAC tumors and is widely used as a clinical biomarker. Elevated serum levels are associated with poor outcomes. However, whether CA19-9 functionally contributes to metastatic progression has not been fully defined, in part because mice lack endogenous CA19-9 expression. Here, using syngeneic murine PDAC cells engineered to express CA19-9, we investigated its functional role in liver metastasis. In splenic injection models, CA19-9 expression markedly increased liver metastatic burden by promoting both metastatic seeding and subsequent metastatic outgrowth. In vitro , CA19-9 enhanced tumor cell adhesion to endothelial cells through interaction with E-selectin. Metastatic seeding of CA19-9-expressing cells was reduced by genetic deletion of E-selectin or antibody neutralization of either CA19-9 or E-selectin in vivo . Therapeutic targeting of CA19-9 with a neutralizing antibody markedly reduced liver metastatic burden after metastatic seeding. CA19-9 expression increased AKT signaling in PDAC cells and liver metastases, and CA19-9 levels correlated with AKT activation in human PDAC tissues. These findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.
    DOI:  https://doi.org/10.64898/2026.04.08.717301
  11. Cancers (Basel). 2026 Mar 26. pii: 1076. [Epub ahead of print]18(7):
    Membrane Curvature and Cancer: Mechanisms, Implications, and Therapeutic Perspectives.
    Alexandros Damalas, Ioannis D Kyriazis, Marijonas Tutkus, Charalampos Angelidis, Varvara Trachana.
      Membrane curvature is a fundamental biophysical property of cellular membranes that underlies essential processes such as vesicle formation, organelle shaping, intracellular trafficking, and membrane scission. While traditionally studied in the context of cell biology and membrane dynamics, membrane curvature is now emerging as a critical, albeit underrecognized, regulator of oncogenic transformation and tumor progression. Curvature not only governs the mechanical properties of the membrane but also influences the spatial localization and activation of key signaling proteins, including Ras family GTPases, whose oncogenic functions are closely dependent on membrane topology. Cancer is frequently associated with disruptions in the regulation of membrane curvature as a result of aberrant lipid metabolism, overexpression of curvature-modulating proteins, and cytoskeletal remodeling. These changes facilitate the hallmarks of malignancy such as uncontrolled proliferation, enhanced motility, immune evasion, metabolic rewiring, and therapy resistance. Notably, recent evidence reveals that curvature acts as a spatial cue for Ras activation, particularly during epithelial-to-mesenchymal transition (EMT), where curvature-driven Ras relocalization amplifies growth factor signaling and promotes metastasis. This review provides a comprehensive overview of the molecular determinants that generate and sense membrane curvature from lipid shape and membrane asymmetry, BAR domain proteins, and actin dynamics, and explores how these mechanisms are hijacked in cancer. We describe the feedback between membrane architecture and oncogenic pathways such as Ras/MAPK and PI3K/AKT, emphasizing the role of curvature in shaping signal transduction platforms. It should be noted that "curvature-driven signaling" is defined as signaling regulation that arises from membrane-geometry-dependent localization, clustering, or activation of signaling proteins, while "curvature-sensitive platforms" refer to membrane subdomains whose specific curvature selectively recruits and stabilizes signaling complexes. Furthermore, we examine how these biophysical alterations impact vesicular trafficking, organelle morphology, and secretion, all of which are co-opted to support tumor development. From a translational standpoint, we assess emerging therapeutic strategies designed to target curvature-regulating factors and leverage membrane topology for precision drug delivery. Innovations in nanomedicine, super-resolution imaging, and curvature-sensing biosensors are also discussed as tools for both diagnostics and therapeutic monitoring. By integrating advances in membrane biophysics, cancer signaling, and bioengineering, this review highlights membrane curvature as a central and actionable dimension of cancer biology.
    Keywords:  EMT; Ras; cancer; caveolae; endocytosis; membrane curvature (MC)
    DOI:  https://doi.org/10.3390/cancers18071076
  12. bioRxiv. 2026 Apr 12. pii: 2026.04.09.717431. [Epub ahead of print]
    Large-scale endoplasmic reticulum membrane solidification spatially organizes proteins under thermal or metabolic stress.
    Paul M Mueller, Melissa R Mikolaj, Elmehdi Belbaraka, Finn Hartstein, Sophia Altinoluk, Bjoern Perder, Philipp Trnka, Robert-William Welke, Heike Naumann, Nina Taudien, Michele Solimena, Severine Kunz, Ilya Levental, Kandice R Levental, Andreas Mueller, Helge Ewers, Kedar Narayan, Oliver Rocks.
      Organelle homeostasis is a key determinant of cellular fitness, yet how cells remodel their membranes in response to environmental change remains unclear. Here, we identify a temperature- and lipid saturation-dependent transformation of endoplasmic reticulum membranes into giant, rigid, multilamellar tubes in cells and in vivo. These "rods" emerge from demixing of saturated lipids into solid-like domains - a previously unrecognised, large-scale endomembrane phase behaviour, fundamentally distinct from the transient liquid-ordered nanodomains of the plasma membrane. ER-tubulating reticulon-homology proteins are excluded from rods; their segregation drives progressive membrane flattening and ultimately multilayered wrapping. Surfactant-producing alveolar type-II lung cells, enriched in saturated lipids, form rods even at 37degC, demonstrating that native lipid metabolism can induce this transformation. This spatially organizing lipid-protein domain interplay may tune the ER tubule/sheet balance and provide a homeoviscous mechanism to preserve fluidity in the cholesterol-poor ER under thermal or metabolic stress.
    DOI:  https://doi.org/10.64898/2026.04.09.717431
  13. J Clin Invest. 2026 Apr 15. pii: e191735. [Epub ahead of print]136(8):
    Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.
    Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji.
      Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.
    Keywords:  Cancer; Cell biology; Drug therapy; Lung cancer; Metabolism
    DOI:  https://doi.org/10.1172/JCI191735
  14. Phys Rev E. 2026 Mar;113(3-1): 034403
    Phase-field approach to cellular blebbing.
    Kaihua Ji, Herbert Levine, Alain Karma.
      Bulges in the plasma membrane of cells known as blebs can form spontaneously in a wide range of biological processes, but what controls their shape and stability remains incompletely understood. To address this we introduce a dual phase-field model with coupled order parameters representing the cell cortex and plasma membrane that can quantitatively model blebbing in three dimensions. Simulations and sharp-interface analyses reveal that, depending on whether blebbing occurs by detachment of the plasma membrane or rupture of the actin cortex, blebs can form discontinuously through a saddle-node bifurcation or continuously with increasing cortical tension. The model predictions are in good quantitative agreement with existing experimental data for laser-induced cortex rupture.
    DOI:  https://doi.org/10.1103/gy7s-m4p9
  15. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00005-1. [Epub ahead of print]205 85-105
    Super resolution microscopy-based assessment of organellar redox-active iron transfer and its relevance for ferroptosis.
    Francesca Rizzollo, Charlotte Cresens, Benjamin Pavie, Pablo Hernandez-Varas, Patrizia Agostinis.
      Intracellular iron is essential for numerous biological processes, yet its redox activity makes it potentially cytotoxic. Because of this, a tight regulation of its cellular compartmentalization is required. Lysosomes and mitochondria play central roles in iron metabolism. Lysosomes are crucial for iron redistribution after its endocytosis, while mitochondria utilize it for heme and Fe-S cluster synthesis. Disruption of the functional crosstalk between these two organelles can lead to iron dyshomeostasis and ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation. Recent evidence highlights the importance of mitochondria-lysosome contact sites (MLCs) in mediating iron trafficking, particularly under pathological conditions. However, studying these nanoscopic, dynamic structures poses significant technical challenges. Here, we describe a novel live-cell imaging protocol combining super-resolution structured illumination microscopy (SIM) with organelle-specific dyes and a selective mitochondrial Fe(II) probe to visualize MLC formation and track iron transfer in real time. This approach enables the precise investigation of subcellular iron dynamics and their implications for ferroptosis and disease.
    Keywords:  Inter-organelle iron transfer; Iron; Lysosomes; Melanoma; Mitochondria; Mitochondria-lysosomes contact sites; Super-resolution structured illumination microscopy
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.005
  16. PNAS Nexus. 2026 Apr;5(4): pgag089
    Aging changes cell mechanics and dynamics associated with cytoplasmic crowding.
    Lani D Lee, Yuechuan Lin, Krishna C Penumatsa, Peter T C So, Ming Guo.
      Aging induces physical changes in organisms, many of which are at the cellular level, but the mechanisms underlying these changes are poorly understood. While the cytoplasm provides a crucial physical environment to host essential cellular processes, how its properties change in aging remains largely unknown. Here, using cells from well-established aging mice models, we first investigate the morphological and dynamic changes of aging cells and how they relate to the physical state of the cytoplasm. We find that aged cells spread larger and rounder and migrate slower than young cells. Using particle fluctuation, optical tweezers, and force spectrum microscopy, we demonstrate that aging increases cytoplasmic stiffness and reduces intracellular movement, even while active intracellular forces increase. In addition, using tomographic phase microscopy, we observe a higher refractive index in aged cells which indicates a denser cytoplasm, hinting that aging causes a more crowded cell interior. This crowding behavior underlines the increased cytoplasmic stiffness and the decreased intracellular movement, thereby influencing the altered cell behavior. Our results imply a crucial physical mechanism behind cellular-level changes due to aging. Though mechanisms behind these observations remain unclear, this understanding of cells' physical nature may support fundamental biological functions explored in aging research.
    Keywords:  aging; cell mechanics; cytoplasm; intracellular crowding
    DOI:  https://doi.org/10.1093/pnasnexus/pgag089
  17. Nature. 2026 04;652(8110): 591-601
    Tumour promotion through the lens of evolution.
    Nuria Lopez-Bigas, Eve Kandyba, Abel Gonzalez-Perez, Paul Brennan, Allan Balmain.
      Almost all tumours carry one or more cancer driver mutations, which are essential for cell transformation. However, recent advances in cancer genomics have demonstrated that normal human tissues contain millions of cells carrying known driver mutations, while preserving homeostasis. Most of these mutated cells will never transform into tumours. Moreover, studies of known or suspected human carcinogens have shown that the majority are not mutagens. These observations suggest that exogenous carcinogenic exposures might increase cancer risk by modifying selective constraints, promoting the expansion of pre-existing clones carrying specific oncogenic mutations. In this Review, we propose a synthesis between ideas put forward almost a century ago based on seminal experiments on carcinogen-induced tumours in mice, observations made by cancer epidemiologists over several decades, and the recent revelation that normal human tissues are a patchwork of mutant clones. The repeated interplay between variation and selection-the first principles of Darwinian evolution-underlies the clonal selection leading to tumorigenesis. A deeper understanding of these processes can enhance prospects for cancer prevention by eliminating or mitigating the effects of environmental or endogenous tumour promoters.
    DOI:  https://doi.org/10.1038/s41586-026-10386-x
  18. Cell. 2026 Apr 16. pii: S0092-8674(26)00285-0. [Epub ahead of print]189(8): 2464-2489
    Cancer neuroscience: The past, the present, and the road ahead.
    Frank Winkler, Sophie Heuer, Ferdinand Althammer, Hellmut Augustin, Filippo Beleggia, Ihsan Ekin Demir, Julian Koenig, Rohini Kuner, Thomas Kuner, Sonja Loges, Michael Platten, Hans Christian Reinhardt, Judith M Rich, Felix Sahm, Ruth Martha Stassart, Vera Thiel, Andreas Trumpp, Varun Venkataramani, Wolfgang Wick, Matthia A Karreman.
      Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.018
  19. Aging Dis. 2026 Apr 03.
    Fine-Tuning Autophagy in Skeletal Muscle: From Homeostasis to Muscle Wasting Disorders.
    Qian Gou, Shi Chee Ong, Wen Xing Lee, Priya D Gopal Krishnan, Hong-Wen Tang.
      Skeletal muscle homeostasis and regenerative capacity depend on efficient protein turnover, organelle quality control, and metabolic adaptation. Disruption of these processes contributes to muscle atrophy and functional decline during aging and various pathological conditions. Autophagy, a lysosome-dependent degradative pathway, maintains muscle integrity by clearing damaged proteins and organelles, preserving mitochondrial quality, and supporting muscle stem cell (MuSC) function. Both insufficient and excessive autophagy are detrimental: reduced flux impairs proteostasis, mitochondrial function, and regeneration, whereas hyperactivation drives excessive protein degradation, mitochondrial loss, and muscle wasting under stress. This review discusses molecular mechanisms regulating autophagy in skeletal muscle, including nutrient- and energy-sensing pathways (AMPK and mTORC1), transcriptional control of autophagy and lysosomal genes, and mitochondrial modulators. Evidence from genetic models and disease contexts indicates that both insufficient and excessive autophagy are associated with muscle degeneration, highlighting the need for balanced autophagic control rather than simple activation or inhibition. Together, these observations support a conceptual framework in which skeletal muscle health depends on maintaining autophagic activity within a context-dependent functional range, although this range is not yet quantitatively defined. This framework provides a useful basis for considering therapeutic strategies targeting muscle wasting.
    DOI:  https://doi.org/10.14336/AD.2026.0170
  20. Autophagy. 2026 Apr 16. 1-3
    TAX1BP1 targets STING1 via microautophagy and Golgiphagy to limit inflammatory signaling.
    Sujit Suklabaidya, Suchitra Mohanty, Edward W Harhaj.
      The CGAS-STING1 pathway plays a key role in detecting cytosolic DNA and initiating immune responses. Excessive STING1 activation can lead to aberrant inflammation and autoinflammatory diseases; therefore, the STING1 degradation pathway is tightly regulated by several negative regulatory mechanisms. In our recent study, we show that the selective autophagy receptor TAX1BP1 functions as a negative regulator of STING1 signaling. TAX1BP1 promotes the degradation of activated STING1 through microautophagy by facilitating the interaction of STING1 with the ESCRT-0 protein HGS, and selective autophagy of the Golgi apparatus in a process known as Golgiphagy. In TAX1BP1-deficient macrophages, STING1 aggregates accumulate at the trans-Golgi network, leading to stronger antiviral and inflammatory responses. These findings support a novel mechanism linking organelle quality control and innate immune regulation, highlighting Golgiphagy as an important feedback mechanism that limits STING1 signaling.Abbreviations: cGAMP: cyclic guanosine monophosphate-adenosine monophosphate; CGAS: Cyclic GMP-AMP synthase; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; ECTV: ectromelia virus; HGS: hepatocyte growth factor-regulated tyrosine kinase substrate; IKK: IκB kinase; IRF3: interferon regulatory factor 3; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TAX1BP1: Tax1 binding protein 1.
    Keywords:  CGAS; Golgiphagy; SQSTM1/p62; STING1; TAX1BP1; microautophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2658230
  21. Nat Methods. 2026 Apr;23(4): 679
    4D whole-cell model of a minimal cell.
    Arunima Singh.
      
    DOI:  https://doi.org/10.1038/s41592-026-03075-0
  22. Chembiochem. 2026 Apr 14. 27(7): e202500850
    Membrane Binding and Pro-Ferroptotic Activity of NQO1.
    Sarah Melissa Strätker, Hartmut Kühn, R Martin Vabulas.
      Peroxidation of polyunsaturated fatty acids in cellular membranes, when extensive and unrepaired, can lead to a form of eukaryotic cell death known as ferroptosis. A complex network of proteins and small molecules has evolved to modulate this peroxidation, thereby suppressing or enhancing ferroptosis. Within this network, the quinone reductase NQO1 has long been recognized for its ability to reduce and regenerate the membrane-resident antioxidant ubiquinone. Surprisingly, recent studies have also implicated NQO1 in pro-ferroptotic processes. Here, we present an experimental model designed to disentangle the opposing activities of NQO1 using a simple in vitro system composed of phospholipid liposomes. The biochemical setup enabled us to recapitulate the membrane association of the normally cytosolic NQO1 and to demonstrate that this association weakens in the presence of its cognate electron donor, NADH. The effect required the C-terminal tail of the enzyme and is likely linked to the higher disorder propensity of its last 50 amino acids. In the presence of NQO1, an increase in iron-driven liposome peroxidation was observed. Without quinone substrates in the system, these results support the idea that the NQO1 cofactor flavin adenine dinucleotide can reduce ferric (Fe3+) iron, thereby promoting reactive oxygen species generation and lipid peroxidation.
    Keywords:  NQO1; ferroptosis; liposomes; peroxidation; phospholipids; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1002/cbic.202500850
  23. Nat Med. 2026 Apr 14.
    Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial.
    Devalingam Mahalingam, Rachna T Shroff, Benedito A Carneiro, Yan Ji, Andrew L Coveler, Andres Cervantes, Vaibhav Sahai, Anne Ploquin, Sandrine Hiret, Noelle K LoConte, Ivor J Percent, Charles D Lopez, Simon Pernot, Petr Kavan, Mary Mulcahy, Ryan Carr, Francis J Giles, Chris Seifarth, Andrey Ugolkov, Taylor Weiskittel, Gil Fine, Mark Jaros, Andrew P Mazar, Tanios S Bekaii-Saab.
      Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the leading causes of cancer-related mortality, but advances in therapeutic treatments remain limited. Elraglusib (9-ING-41), an inhibitor of GSK-3β, exhibits a multimodal mechanism of action based on antitumor activity in preclinical models of cancer, including pancreatic. The efficacy and safety of elraglusib with gemcitabine plus nab-paclitaxel (GnP) were assessed in patients with previously untreated mPDAC. In an open-label, international, multicenter, phase 2 study, patients were randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (OS) and 1-year survival rate. The prespecified modified intention-to-treat population included 155 patients on elraglusib/GnP and 78 on GnP. As of the data cutoff of 27 April 2025, elraglusib/GnP improved median OS by 2.9 months and decreased the risk of death by 38% versus GnP (median OS 10.1 months versus 7.2 months, respectively (hazard ratio 0.62; 95% confidence interval 0.46 to 0.84; P = 0.01)). The 1-year survival rates were 44.1% versus 22.3%, respectively. The safety profile of elraglusib/GnP was manageable. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) with elraglusib/GnP versus GnP alone were neutropenia (52.3% versus 30.8%), anemia (25.2% versus 29.5%) and fatigue (16.8% versus 5.1%). Explorative correlative analyses demonstrated that baseline circulating immune-related factors (that is, CXCL2 and TRAIL ligands) were associated with improved survival in the elraglusib/GnP arm. Treatment was accompanied by increases in intratumoral cytotoxic immune cell populations. Together, these findings support the clinical activity of elraglusib/GnP as first-line treatment in mPDAC and provide a biological context for the observed survival benefit. Based on the results of this phase 2 trial, a phase 3 trial is being planned. ClinicalTrials.gov registration: NCT03678883.
    DOI:  https://doi.org/10.1038/s41591-026-04327-4
  24. Phys Rev E. 2026 Mar;113(3-1): 034405
    Controlling tissue size by active fracture.
    Wei Wang, Brian A Camley.
      Groups of cells, including clusters of cancerous cells, multicellular organisms, and developing organs, may both grow and break apart. What physical factors control these fractures? In these processes, what sets the eventual size of clusters? We first develop a one-dimensional framework for understanding cell clusters that can fragment due to cell motility using an active particle model. We compute analytically how the break rate of cell-cell junctions depends on cell speed, cell persistence, and cell-cell junction properties. Next, we find the cluster size distributions, which differ depending on whether all cells can divide or only the cells on the edge of the cluster divide. Cluster size distributions depend solely on the ratio of the break rate to the growth rate-allowing us to predict how cluster size and variability depend on cell motility and cell-cell mechanics. Our results suggest that organisms can achieve better size control when cell division is restricted to the cluster boundaries or when fracture can be localized to the cluster center. Additionally, we derive a universal survival probability for an intact cluster S(t)=e^{-k_{d}t} at steady state if all cells can divide, which is independent of the rupture kinetics and depends solely on the cell division rate k_{d}. Finally, we further corroborate the one-dimensional analytics with two-dimensional simulations, finding quantitative agreement with some-but not all-elements of the theory across a wide range of cell motility. Our results link the general physics problem of a collective active escape over a barrier to size control, providing a quantitative measure of how motility can regulate organ or organism size.
    DOI:  https://doi.org/10.1103/dk15-hwzg
  25. Redox Biol. 2026 Apr 08. pii: S2213-2317(26)00163-1. [Epub ahead of print]93 104165
    Txnrd2 loss in skeletal muscle causes muscle atrophy and drives leanness and obesity resistance.
    Claudia Kiermayer, Rebecca Erdelen, Sonja C Schriever, Ramona Böhm, Cornelia Prehn, Anna Artati, Maximilian Kleinert, Manuel Miller, Kenneth A Dyar, Roland M Schmid, Paul T Pfluger, Jerzy Adamski, Markus Brielmeier.
      The mitochondrial selenoenzyme thioredoxin reductase 2 (TXNRD2) plays a critical role in redox homeostasis and reactive oxygen species (ROS) scavenging. While heart-specific deletion of Txnrd2 in mice resulted in cardiac dysfunction, TXNRD2 function in skeletal muscle, the major component of lean body mass, remains unclear. In human GWAS the TXNRD2 locus is associated with total lean mass. Here, we show that Txnrd2 muscle-specific knockout (mTKO) induces a lean phenotype characterized by muscle atrophy and diminished adipose tissues. mTKO mice were resistant to weight gain on standard and high-fat diet. Whole body glucose clearance was increased, and ATP levels in muscle were decreased, suggesting impaired mitochondrial energy production. Transcriptomic and metabolomic analyses revealed alterations in one-carbon metabolism and related pathways. Despite elevated glutathione levels, changes in key factors of cellular detoxification were consistent with compromised antioxidant defence system. In sum, we unravel that Txnrd2 deficiency in skeletal muscle rewires whole-body energy metabolism through mitochondrial dysfunction and impaired redox capacity.
    DOI:  https://doi.org/10.1016/j.redox.2026.104165
  26. Mol Oncol. 2026 Apr 17.
    Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance.
    Kanishka Tiwary, Jose Javier Bravo-Cordero.
      Metastasis remains the leading cause of cancer-related mortality. Even after major advances in early detection and systemic therapies, long-term disease recurrence frequently arises from the presence of dormant disseminated tumor cells (DTCs) at distant sites. Dormant DTCs disseminate from the primary tumor and reside in secondary organs in a reversible quiescent state characterized by minimal proliferation, enabling resistance to therapies that target actively dividing cells. Despite their inactivity, dormant DTCs are far from inert. Dormant DTCs dynamically interact with the surrounding tumor microenvironment (TME), including stromal, vascular, and immune components, to establish niches that maintain quiescence while limiting immune detection. While the mechanisms by which proliferating cancer cells evade immune surveillance have been extensively studied, the processes governing immune regulation, immune-mediated dormancy, and immune evasion of dormant DTCs remain incompletely integrated across literature. In this review, we explore recent advances describing how microenvironmental cues and immune pressures converge on tumor cell-intrinsic programs to sustain dormancy, promote immune tolerance, and enable long-term survival of DTCs across different organs and cancer types. We further discuss conditions that disrupt this equilibrium and drive escape from dormancy, as well as emerging therapeutic strategies aimed at eliminating or controlling dormant DTCs by targeting dormancy-specific immune and microenvironmental interactions.
    Keywords:  disseminated tumor cells; immune evasion; metastatic niche; quiescence; tumor dormancy; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70259
  27. Phys Rev E. 2026 Mar;113(3-1): 034404
    pH gradient-driven deformation of a crista-like vesicle.
    Yorgos Chatziantoniou, Hélène Berthoumieux.
      The inner membrane of mitochondria presents folds, the cristae, which are the production place of ATP. This synthesis is catalized by transmembrane proteins and relies on a flow of protons confined to the surface of the membrane. We posit that, in turn, the proton flux shapes the crista membrane in a way that suits these proteins. To study this hypothesis, we model a crista as a spherical vesicle submitted to a diffusive proton gradient flowing from the poles to the equator. Using Helfrich model, we introduce a pH-dependent spontaneous curvature for the membrane and determine the shape of the vesicle, in the regime of small deformations. We show that the pH gradient can produce shapes featuring flat zones at the poles and curved zones at the equator. These correspond to the geometry of the proteins involved in the process. Based on biophysical arguments, we define a functionality score for the vesicle and construct a phase diagram identifying the zones of "well-functioning" cristae, which we compare to experimental measurements.
    DOI:  https://doi.org/10.1103/g6fm-frk4
  28. Nat Methods. 2026 Apr;23(4): 675
    Appeals: what, why, when, how.
      
    DOI:  https://doi.org/10.1038/s41592-026-03081-2
  29. Cell. 2026 Apr 16. pii: S0092-8674(26)00323-5. [Epub ahead of print]189(8): 2209-2213
    Hallmarks of cancer research: Enabling transformative discovery through global team science.
    Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Andrew Kurtz, Dinah S Singer, David Scott.
      Since the original Hallmarks of Cancer, our understanding of the complexity of the disease has expanded dramatically. Researching cancer is no longer simply a question of ever more sophisticated experiments but of delivering science in an evolving and complex system. Here, we discuss how to support global team science and catalyze transformative discovery, drawing on our experience from the Cancer Grand Challenges initiative.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.022
  30. Cell. 2026 Apr 16. pii: S0092-8674(26)00326-0. [Epub ahead of print]189(8): 2416-2440
    Mapping intratumor heterogeneity across layers for advancing immunotherapy.
    Jean-Christophe Marine, Osnat Bartok, Shira Sagie, Pietro Paolo Vitiello, Alberto Bardelli, Chen Weller, Tian-Gen Chang, Claudia Tonelli, Stefani Spranger, Eytan Ruppin, Yardena Samuels.
      Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional, proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is increasingly clear that non-mutational heterogeneity and plasticity generate dynamic cancer cell states with distinct immune visibility. These layers of complexity converge on the immunopeptidome, the repertoire of peptides displayed by major histocompatibility complex molecules through which tumor cells are surveyed by T cells. Variation in antigen processing, presentation, and peptide abundance across cancer clones and cell states yields spatially and temporally distinct immunological niches that shape immune recognition and therapeutic response. Here, we summarize how multidimensional ITH manifests across cancer types and constrains immunotherapy efficacy. We propose that integrating measurements across layers is a promising direction for improving biomarker identification and informing more precise immune-based treatment strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.025
  31. Nature. 2026 Apr 15.
    Emergence of oncofetal plasticity is ubiquitous in early colorectal cancers.
    Julian R Buissant des Amorie, Joris H Hageman, Sascha R Brunner, Suzanne E M van der Horst, Maria C Puschhof, Arne van Hoeck, Inge van Lierop, Sjors Middelkamp, Lisa van der Schee, Sven van Kempen, Folkert Morsink, Robin Geene, Sander Mertens, David S Cavigelli, Ingrid Verlaan-Klink, Lianne J Kraaier, Jorieke Salij, Renate Bezemer, Onno Kranenburg, Miangela M Laclé, Leon M G Moons, Hugo J G Snippert.
      Metastasis formation is classically considered a late-stage event in colorectal cancer evolution. Yet the time and spatial patterning by which metastatic competence is acquired remain poorly understood1,2. Here we show that metastasis-associated oncofetal cell states already emerge at the earliest stages of colorectal cancer, concurrent with invasive front formation. However, although necessary for metastasis, we detect them ubiquitously among early non-metastatic cancers, highlighting extra bottlenecks such as immune evasion. To understand how oncofetal cells first emerge, we generated multiregional organoid models that reflect successive tumour progression stages within individual early-stage colorectal cancers. Whole-genome sequencing and growth factor-dependency assays exclude tumour cell-intrinsic acquired traits. By contrast, single-cell spatial atlases of the tumour microenvironment before and after malignant transformation revealed stereotypic patterning of fibroblast subtypes resembling normal tissue architecture, resulting in distinct regional microenvironments. At the onset of malignant growth into the submucosa, the first cancer-associated fibroblasts to appear strongly resemble submucosal trophocytes and colocalize with oncofetal cell states at invasive fronts. Functionally, fibroblast-organoid cocultures confirm that these trophocyte-like cancer-associated fibroblasts induce plastic transitioning to oncofetal states. Thus, interactions between tumour and submucosal fibroblasts directly following malignant transformation dictate the timing and location at which oncofetal plasticity first occurs during colorectal cancer progression.
    DOI:  https://doi.org/10.1038/s41586-026-10344-7
  32. Mol Cell Proteomics. 2026 Apr 15. pii: S1535-9476(26)00065-4. [Epub ahead of print] 101569
    Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.
    Colin Zenge, Brittany Q Pham, Kihong Nam, Elana Apfelbaum, Heeseon An, Alban Ordureau.
      Altered metabolism is a hallmark of cancer, making metabolic enzymes attractive therapeutic targets. However, metabolic inhibitors have shown limited clinical success, partly due to differences between standard culture media and physiological nutrient conditions. Human plasma-like medium (HPLM) better recapitulates in vivo metabolite concentrations, yet its effects on cellular proteomes remain poorly characterized. We performed comprehensive TMTpro-based quantitative proteomics and phosphoproteomics across nine cancer cell lines cultured in DMEM or HPLM, consistently quantifying over 10,000 proteins and 24,000 phosphorylation sites across all three biological replicates with high reproducibility. Physiological media induced profound cell-type-specific remodeling of metabolic networks, mitochondrial proteomes, and signaling pathways. While decreased mTORC1 and CDK activity represented universal responses across all cell lines, metabolic enzyme expression exhibited striking heterogeneity. Enzymes in folate metabolism and pyrimidine salvage pathways showed consistent reductions across all cell types, indicating that drug responses may vary with media choice. Mitochondrial proteome composition and morphology displayed cell-type-specific adaptations. Phosphoproteomic analysis revealed kinase signaling networks underlying these metabolic changes. This dataset, accessible via an interactive web application, provides a resource for metabolic research using physiological media, highlighting substantial cell-type-specific variability in how media affect proteomes and signaling pathways.
    Keywords:  CDK activity; Cancer cell metabolism; Physiological Media; Proteomics; mTORC1 signaling
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101569
  33. Cell. 2026 Apr 16. pii: S0092-8674(26)00328-4. [Epub ahead of print]189(8): 2218-2231
    Tackling the complexity of cancer with generative models.
    Ashley Mae Conard, Madeline Hughes, James Hall, Neil Tenenholtz, Eric Zimmermann, Lorin Crawford, Ava P Amini, Kristen Severson.
      The Hallmarks of Cancer framework has played a seminal role in developing our understanding of cancer biology. By design, these hallmarks abstract cancer into a common set of functional capabilities. The hallmarks thus constitute an intentionally reductionist framework that has unified diverse observations and yielded valuable mechanistic insight, while leaving unresolved how these processes interact across scales. Complementary tools are therefore needed to capture cancer's inherently complex, multimodal, and multiscale nature. Here, we posit that generative models, built on the recent advances of artificial intelligence, are the key technology to capture this complexity and to thereby improve how we diagnose, understand, and intervene in cancer. Specifically, because of their ability to recognize complex patterns, process unstructured inputs, and synthesize multimodal inputs, generative models are poised to usher in a new era of biological discovery and clinical care. Ultimately, we envision a synergistic cycle wherein generative models of cancer and the Hallmarks of Cancer complement one another, the former driving hypothesis generation and discovery and the latter guiding the prioritization and development of new measurement tools.
    Keywords:  Hallmarks of Cancer; artificial intelligence; generative models; multimodal learning
    DOI:  https://doi.org/10.1016/j.cell.2026.03.027
  34. Cancer Discov. 2026 Apr 13. OF1-OF4
    Training the Next Generation of AI-Enabled Cancer Scientists.
    Olivier Elemento, Paraskevi Giannakakou.
      Despite unprecedented opportunities at the convergence of artificial intelligence (AI) and cancer research, few scientists possess fluency in both domains. We propose a six-principle framework for training "AI-oncology bilingual" scientists who can bridge this gap and translate AI-driven discoveries into improved patient outcomes.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2087
  35. FEBS Lett. 2026 Apr 15.
    An isoform of 14-3-3 protein regulates transbilayer lipid movement at the plasma membrane.
    Akiko Yamaji-Hasegawa, Akira Hattori, Masafumi Tsujimoto, Toshihide Kobayashi.
      Exogenous phosphatidylserine (PS) is cytotoxic to Chinese hamster ovary (CHO) cells with a PS-resistant CHO cell mutant exhibiting impaired transbilayer movement of a fluorescent PS analog at the plasma membrane. Here, we demonstrate that both mRNA and protein levels of 14-3-3 zeta are markedly reduced in this mutant, while knockdown of 14-3-3 zeta in wild-type CHO cells confers partial resistance to exogenous PS. Consistently, these knockdown cells display defective transbilayer movement of 1-palmitoyl-2-{6-[(7-nitro-1,3-benz-2-oxadiazol-4-yl) amino] hexanoyl}-sn-glycero-3-phosphoserine (C6-NBD-PS). However, 14-3-3 zeta knockdown does not further enhance PS resistance in ATP11C-deficient cells. These findings indicate that 14-3-3 zeta plays a regulatory role in ATP11C-dependent transbilayer movement of PS at the plasma membrane. Impact statement 14-3-3ζ regulates ATP11C-dependent phosphatidylserine (PS) transbilayer movement at the plasma membrane. Reduced 14-3-3ζ impairs PS flipping and confers resistance to exogenous PS in CHO cells, identifying 14-3-3ζ as a key modulator of phospholipid asymmetry and lipid-induced cytotoxicity.
    Keywords:  14‐3‐3ζ; flip‐flop; fluorescent lipid analog; phosphatidylserine; transbilayer lipid movement
    DOI:  https://doi.org/10.1002/1873-3468.70338
  36. Cell Death Discov. 2026 Apr 11. pii: 182. [Epub ahead of print]12(1):
    Bacterial protein-oleate complexes induce ferroptosis-like cell death in colorectal cancer cells by disrupting cell membranes and inhibiting the β-catenin-GPX4 axis.
    Naeem Ullah, Abdelbasset Yabrag, Amjad Ali, Aftab Nadeem.
      The tumoricidal activity of human α-lactalbumin complexes, such as HAMLET and its α-helical domain with sodium oleate, is well-documented. However, the potential of bacterial α-helical proteins to form analogous anticancer complexes remains unexplored. In the current study, we demonstrate that α-helical proteins of bacterial origin can form tumoricidal complexes with sodium oleate. Using non-hemolytic toxin A (NheA), an inactive component of the native tripartite (NheABC) toxin complex from Bacillus thuringiensis, we show that NheA, upon mixing with sodium oleate (NheA-O), forms potent tumoricidal complexes against colorectal cancer cells. The NheA-O complex binds to the plasma membrane of tumor cells, disrupting the function of cellular organelles and ultimately causing cell death. Mechanistically, NheA-O induces ACSL4 and suppresses GPX4 expression, which ultimately leads to the accumulation of lipid peroxidation, following suppression of β-catenin signaling. The suppression of β-catenin signaling and its target proteins ultimately leads to suppression of colorectal cancer tumorigenesis. Functionally, NheA-O inhibits tumor cell migration, spheroid formation, clonogenic potential, ATP production and induces lipid peroxidation. These findings establish that bacterial α-helical proteins, like their human counterparts, can be engineered to form tumoricidal complexes with sodium oleate. Our work highlights NheA-O as a novel candidate that causes activation of ferroptosis-like cell death in target cancer cells, leading to intracellular organelles dysfunction. Moreover, NheA-O activity synergizes with RSL3, and NheA-O mediated cell death is antagonized by Fer-1, indicating the role of NheA-O in inducing ferroptosis-like cell death. Overall, these results describe NheA-O as a novel therapeutic agent to combat tumorigenesis by targeting tumor cell membrane and proteasomal degradation of GPX4 to trigger ferroptosis-like cell death and expands the paradigm of tumoricidal protein-lipid complexes functionality across biological kingdoms.
    DOI:  https://doi.org/10.1038/s41420-026-03097-9
  37. Nat Methods. 2026 Apr;23(4): 678
    Establishing whole-body cellomics.
    Fariha Rahman.
      
    DOI:  https://doi.org/10.1038/s41592-026-03072-3
  38. Nat Cell Biol. 2026 Apr 13.
    Lipid-trap mass spectrometry identifies lipid-protein interactions in cells.
    Andrea Paquola, Clare E Benson, Smita Eknath Desale, Cagakan Ozbalci, Elisabeth M Storck, Stephen J Terry, Bhagyashree Dasari Rao, Kelechi N Nwite, Federica Ferrentino, Ulrike S Eggert.
      Cells actively maintain complex lipidomes that encompass thousands of lipids; however, many of the roles of these lipids remain unexplored. Specific interactions between lipids and membrane proteins are a likely reason for lipidome complexity. Here we report the development of a technique, named lipid-trap mass spectrometry (LTMS), to systematically study lipid-protein interactions directly captured from mammalian cells. LTMS uses immunoprecipitation of GFP-tagged proteins expressed in HeLa cells, followed by lipidomic analysis of lipids bound to the GFP-tagged protein. We applied LTMS to cell division to illustrate the technique. We chose this process because membranes regulate their lipid composition as they undergo major changes during cytokinesis, and many cytokinetic proteins, including RACGAP1 and ESCRT-III components CHMP4B and CHMP2A, are membrane-associated. Using LTMS, we found that RACGAP1 and CHMP4B associate with specific lipid species in dividing compared with non-dividing cells. We expand our understanding of lipid diversity during cell division and present a general approach to explore lipid-protein interactions to further our knowledge of the roles of lipids in mammalian cells.
    DOI:  https://doi.org/10.1038/s41556-026-01928-6
  39. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00013-0. [Epub ahead of print]205 63-83
    Implementation of the FENIX assay to assess the anti-ferroptotic properties of test compounds.
    Juliana A Hüther, Melodie Mallais, Markus Rehm, Derek A Pratt.
      Ferroptosis is an iron-dependent form of regulated cell death characterized by the uncontrolled accumulation of lipid peroxides, primarily within phospholipid membranes. This oxidative process, driven by a radical-mediated chain reaction known as autoxidation, plays a central role in numerous pathological conditions including neurodegeneration, ischemia-reperfusion injury, and cancer. Pharmacological inhibition of lipid peroxidation by radical-trapping antioxidants (RTAs) has thus emerged as a promising strategy for therapeutic intervention. However, conventional 'antioxidant assays' such as 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) or oxygen radical absorbance capacity (ORAC) are inadequate for assessing reactivity toward lipid peroxyl radicals, limiting their utility in ferroptosis research. To address this gap, the Fluorescence-ENabled Inhibited autoXidation (FENIX) platform was developed as a physiologically relevant, high-throughput assay system for the mechanistic and kinetic characterization of lipid peroxidation inhibitors. FENIX-1 quantifies RTA activity by measuring rate constants for RTA-lipidperoxyl radical reactions initiated by a highly lipid-soluble radical initiator in liposomal systems wherein a fluorescent reporter is co-autoxidized along with the lipids. In FENIX-2 lipid peroxidation is initiated via iron-mediated decomposition of pre-formed phospholipid hydroperoxides, enabling the study of both RTA and non-RTA inhibitors, including iron chelators and peroxidase mimics. Together, these assays are complementary and mechanistically informative platforms for the identification and evaluation of inhibitors of lipid peroxidation and - by extension - ferroptosis. Here, we present a detailed overview and standardized protocols for both FENIX-1 and FENIX-2, with the aim of encouraging their application in lipid peroxidation research, ferroptosis modulation, and redox-targeted drug discovery.
    Keywords:  Ferroptosis inhibition assay; Inhibition rate constant (k(inh)); Lipid peroxidation kinetics; Liposomal autoxidation model; Radical-trapping antioxidant screening; STY-BODIPY fluorescence assay
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.013
  40. Nat Biotechnol. 2026 Apr;44(4): 500
    FDA approves wearable device for pancreatic cancer.
      
    DOI:  https://doi.org/10.1038/s41587-026-03102-7
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