bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–10–04
38 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia.
  2. Activity over Abundance: ADAMTSL4 Unlocks Latent TGFβ1 in Cancer Cachexia.
  3. Allele-Specific Mechanisms Guide Salvage Therapy to Overcome Daraxonrasib Resistance in Pancreatic Cancer.
  4. Quality over Quantity: Dietary Fatty Acid Composition Shapes Pancreatic Tumorigenesis.
  5. A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.
  6. Quantification of lipid sorting during clathrin-mediated endocytosis.
  7. Serpins Establish Fibrin-Rich Suppressive Niches in Pancreatic Cancer.
  8. Motixafortide, cemiplimab, gemcitabine and nab-paclitaxel in metastatic pancreatic cancer: a single-arm phase 2 study with single-cell correlatives.
  9. A transient MXD4-dependent proliferative pause enables survival of brain micrometastases.
  10. Targeted extracellular degradation of LRP8 promotes ferroptosis in cancer cells.
  11. The physicochemical design, structure and permeability of the JCVI-syn3A minimal cell membrane.
  12. Tumor cell-intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer.
  13. Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
  14. Redox activation of ATG5 licenses autophagy upon nutrient restriction.
  15. Biophysical and molecular mechanisms of lysosomal mechanoresilience: Membrane tension, TMEM63A, and cellular injury.
  16. An extramedullary bone model of metastatic dormancy reveals an increased rate of metastatic reactivation upon distant insults.
  17. Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx.
  18. Exercise Modulates Microbial Metabolites and Induces Stromal Remodeling in Pancreatic Cancer.
  19. Targeting Distinct Cell Cycle Nodes Overcomes RAS Inhibitor Resistance.
  20. The Phospholipase A2 Superfamily in Health and Disease: From Lipid Signaling to Inflammation, Cancer, and Neurodegeneration.
  21. Daraxonrasib: The first-in-class RAS(ON) multi-selective inhibitor approved for treatment of metastatic pancreatic adenocarcinoma.
  22. Curved adhesions resist disruption by high-affinity αv-integrin inhibitors.
  23. Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance.
  24. ArchMap is a web-based platform for reference-based analysis of single-cell datasets.
  25. Mouse lymph node colonization models predict human tumor metastasis in melanoma.
  26. Real-Time Monitoring of Mass and Mechanical Properties in Single Cells and Multicellular Spheroids.
  27. Cellular senescence: six decades of discovery and reinvention.
  28. A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
  29. On the Inhibition of Lipid Peroxidation and Ferroptosis by Fatty Acids.
  30. Sequestosome 1 (SQSTM1/p62) at the nexus of genome integrity maintenance, proteostasis regulation and organellar homeostasis.
  31. Multiomic analysis of malignant ascites defines RORC-expressing dendritic cells at sites of metastasis.
  32. Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
  33. Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer.
  34. Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer.
  35. CytoVI: deep generative modeling of antibody-based single cell data.
  36. Electric-field manipulation of giant vesicles: new frontiers in membrane electromechanics.
  37. FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non-small cell lung cancer.
  38. The fruitfly Drosophila melanogaster as an in vivo model of ferroptosis.
  1. bioRxiv. 2026 Sep 09. pii: 2026.09.04.748998. [Epub ahead of print]
    Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia.
    Gabriele Guarnaccia, Jimmy Massenet, Alessandra Cecchini, Elena Guarnaccia, Beatrice Silvestri, Chiara Nicoletti, Jesus R Barajas, David Sala, Marcos G Teneche, Brightany Li, Luca Caputo, Cedomir Stamenkovic, Tatiana M Moreno, Rabi Murad, Shawn Delaware, Daphne Mayer, Yijuan Zhang, Priyanka Gupta, Alexandre R Colas, Alessandro Vasciaveo, Caroline Kumsta, Peter D Adams, Will Wang, Cesare Gargioli, Commisso Cosimo, Pier Lorenzo Puri, Alessandra Sacco.
      Cancer cachexia limits treatment tolerance and survival in pancreatic ductal adenocarcinoma (PDAC), yet the tumor-derived signals driving tissue dysfunction remain poorly understood. Here, we identify serum amyloid A1 (SAA1) as a mediator of tumor- to-host communication acting through Toll-like receptor 4 (TLR4). Tumor-derived SAA1 was elevated in human PDAC and in a mouse PDAC model and disrupted both myofiber and muscle stem cell (MuSC) homeostasis. Genetic reduction of tumor-derived SAA1 uncoupled tumor progression from host wasting, preserving muscle mass and function and prolonging survival without affecting primary tumor growth. Mechanistically, SAA1-TLR4 signaling drove multicellular remodeling of the skeletal muscle microenvironment. Therapeutic TLR4 inhibition after cachexia onset restored muscle mass, function and MuSC abundance and prolonged survival independently of tumor growth. Conservation of SAA1-TLR4 signaling in human skeletal muscle identifies a therapeutically actionable tumor-host pathway and demonstrates that host deterioration can be targeted independently of tumor progression.
    DOI:  https://doi.org/10.64898/2026.09.04.748998
  2. Cancer Discov. 2026 Oct 01. 16(10): 1964-1966
    Activity over Abundance: ADAMTSL4 Unlocks Latent TGFβ1 in Cancer Cachexia.
    Ying Liu, Tobias Janowitz.
      Cancer cachexia is increasingly recognized as a coordinated, tumor-induced, unsustainable alteration in interorgan communication. Machado and colleagues identify a new molecular mechanism that promotes cachexia, in which tumor-secreted ADAMTSL4 drives tissue wasting by promoting local activation of latent TGFβ1, revealing post-secretory control of ligand activation as a potential therapeutic vulnerability in cancer cachexia. See related article by Machado et al., p. 2172.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1661
  3. Cancer Res. 2026 Sep 30. OF1-OF21
    Allele-Specific Mechanisms Guide Salvage Therapy to Overcome Daraxonrasib Resistance in Pancreatic Cancer.
    Daniel Dorbin, Juliannie Herrera, Raven Davidson, Naveen Kumar Chandrashekar, Gabrielle Scheuber, Priyanga Jayakrishnan, Christabelle Rajesh, Grayson Johnson, Jason Yuan, Matthew A Sochor, John F Langenheim, Mohammed Aldakkak, Charles Messerly, Jacquelyn Wittmann, Aniko Szabo, Forough Azam Sayahpour, Nathan L Atallah, Francis C Peterson, Brian F Volkman, Mahmoud Ali, Eugene Ke, Douglas B Evans, Susan Tsai, Nikki K Lytle, Y David Seo, Razelle Kurzrock, G Aaron Hobbs, Mandana Kamgar, Thomas McFall.
      Clinical-grade RAS inhibitors raise an unresolved question about whether KRAS alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multiselective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited mutant KRAS primarily through steric occlusion of effector binding while engaging wild-type RAS (RASWT) only modestly (∼20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib-resistant KRASG12R pancreatic ductal adenocarcinoma (PDAC) cells utilized EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease in cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to EGFR/RASWT dependence conferred sensitivity to trametinib. As clinical confirmation, a patient with KRASG12R PDAC who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived tumoroid modeling predicted sensitivity to trametinib-based combination therapy. Despite the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control, and this patient ultimately achieved 40 months of overall survival, far exceeding the 8 to 12 months median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.
    SIGNIFICANCE: Daraxonrasib resistance emerges through allele-specific routes, with CypA being downregulated in KRASG12D and reliance on EGFR/RASWT in KRASG12R cancer cells, informing mechanism-based therapeutic strategies for patients who progress on RAS inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1181
  4. Cancer Discov. 2026 Oct 01. 16(10): 1961-1963
    Quality over Quantity: Dietary Fatty Acid Composition Shapes Pancreatic Tumorigenesis.
    Yu-Jin Jeong, Evan C Lien.
      Obesity and high dietary fat consumption are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC), and Ruiz and colleagues show that in addition to total fat consumption, distinct types of dietary fat contribute differently to tumor initiation in murine PDAC models. Diets rich in monounsaturated fatty acids enhance tumor progression, whereas dietary polyunsaturated fatty acids suppress tumorigenesis by increasing pancreatic cell susceptibility to lipid peroxidation and ferroptosis. See related article by Ruiz et al., p. 2108.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1528
  5. Nat Commun. 2026 08 31. pii: 10374. [Epub ahead of print]17(1):
    A lipid transfer-dependent feedback loop activates ATG9A compartments in autophagy initiation.
    Elisabeth Holzer, Justyna Sawa-Makarska, Daniel Bernklau, Julia Romanov, Martina Schuschnig, Sascha Martens.
      Autophagy degrades cellular material by sequestering it within autophagosomes, which form de novo from precursors called phagophores. Phagophore assembly and expansion require ATG9A-positive seed compartments, the lipid transfer protein ATG2A, and the class III phosphatidylinositol 3-phosphate kinase complex I (PI3KC3-C1). PI3KC3-C1 synthesizes phosphatidylinositol 3-phosphate (PI3P), a key lipid that drives downstream processes for phagophore expansion, including ATG8 lipidation. We find that ATG9A compartments contain only traces of phosphatidylinositol (PI), likely insufficient for efficient PI3P production or recruitment of PI3P-binding effectors. Nevertheless, ATG2A is recruited to these compartments and mediates lipid transfer, including PI, into them. Remarkably, even without detectable PI3P, ATG9A compartments are direct substrates for ATG8 lipidation, and ATG8 proteins themselves enhance ATG2A-mediated lipid transfer. In cells, ATG2A is essential for the appearance of PI3P on ATG9A compartments. Our findings support a model in which a lipid transfer-driven feedback loop activates ATG9A compartments for phagophore expansion.
    DOI:  https://doi.org/10.1038/s41467-026-77368-5
  6. Nat Cell Biol. 2026 Sep 29.
    Quantification of lipid sorting during clathrin-mediated endocytosis.
    H Mathilda Lennartz, Susana da Costa Nunes, Kristin Böhlig, Aditya Chhatre, Radek Šachl, Sascha M Kuhn, Lior Moneta, Pavel Barahtjan, Wan Yee Yau, Juan M Iglesias-Artola, Martin Hof, Lukáš Opálka, Carl D Modes, Alf Honigmann, André Nadler.
      Clathrin-mediated endocytosis is a major transport route for proteins from the plasma membrane to the interior of the cell. While the recruitment of cargo proteins to clathrin-coated pits is well understood, it remains an open question whether lipids are also sorted by this process. Here, to address this question, we combined super-resolution stimulated emission depletion imaging of bifunctional lipid probes with mathematical modelling. Quantification of ten different lipid species revealed significant differences in pit partitioning, ranging from slight enrichment to moderate exclusion. We find that the lipid asymmetry in the plasma membrane is sufficient to explain the observed trend. Taken together, our findings imply that clathrin-mediated endocytosis has a minor selectivity for cytoplasmic leaflet lipids, but overall does not substantially contribute to lipid sorting compared with non-vesicular trafficking.
    DOI:  https://doi.org/10.1038/s41556-026-02068-7
  7. Cancer Discov. 2026 Oct 02. OF1
    Serpins Establish Fibrin-Rich Suppressive Niches in Pancreatic Cancer.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-088
  8. Nat Commun. 2026 08 21. pii: 10350. [Epub ahead of print]17(1):
    Motixafortide, cemiplimab, gemcitabine and nab-paclitaxel in metastatic pancreatic cancer: a single-arm phase 2 study with single-cell correlatives.
    Alexander G Raufi, Edridge K D'Souza, Michael S May, Sarah Sedycias, Ilenia Pellicciotta, Samuel Pan, Shikun Wang, Carmine Palermo, Steven Sastra, Naomi Sender, Isabelle Ross, Li Li, Karan Luthria, Parin Shah, Somnath Tagore, Zachary H Walsh, Andrew Turk, Bircan Sema, Alina Iuga, Sun Dajiang, Michael D Kluger, Beth A Schrope, Dane Brown, Tito Fojo, Juan-Manuel Schvartzman, Yoanna Pumpalova, Ryan H Moy, Susan Bates, Linda Wu, Hanina Hibshoosh, Aik Choon Tan, Gary K Schwartz, John A Chabot, Kenneth P Olive, Benjamin Izar, Gulam A Manji.
      The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis drives immune exclusion in pancreatic ductal adenocarcinoma (PDA). Building on our preclinical data, we conducted the first stage of an open-label, single-arm phase 2 clinical trial combining CXCR4 inhibition (motixafortide), PD-1 blockade (cemiplimab), and chemotherapy (gemcitabine/nab-paclitaxel [GN]; MCGN) in 11 treatment-naïve patients with metastatic PDA ( NCT04543071 ). The primary endpoint, objective response rate, was 64% partial response and 55% confirmed partial response per Response Evaluation Criteria in Solid Tumors. Secondary endpoints include median progression-free survival of 9.7 months (95% confidence interval [CI]: 5.9-not reached [NR]), overall survival of 10.1 months (95% CI: 9.3-NR), duration of response of 8.2 months, and 91% disease control rate. One patient achieved a pathological complete response after pancreatoduodenectomy and hepatectomy, remaining disease-free for 18 months without adjuvant therapy. Exploratory single-nucleus RNA-sequencing of serial biopsies showed reduced tumor heterogeneity, depletion of epithelial-to-mesenchymal transitional states, and enrichment of CXCL12+ cancer-associated fibroblasts in responders relative to resistant patients. MCGN also induced tumor inflammation as confirmed by tissue staining and T cell rescue. A multicenter randomized phase 2 trial comparing MCGN to GN in patients with treatment-naïve metastatic PDA is ongoing.
    DOI:  https://doi.org/10.1038/s41467-026-76559-4
  9. Cancer Cell. 2026 Sep 28. pii: S1535-6108(26)00399-5. [Epub ahead of print]
    A transient MXD4-dependent proliferative pause enables survival of brain micrometastases.
    PEACE Consortium
      Successful metastatic colonization requires cancer cells to survive multiple stresses during early organ adaptation, yet how metastasis-initiating cells overcome this bottleneck remains unknown. Here, we identify a transient MXD4-dependent proliferative pause that enables aggressive cancer cells to survive early brain colonization. Before vascular co-option-associated outgrowth, metastatic cells temporarily restrain proliferation through the MYC antagonist MXD4, buffering stresses encountered after extravasation. Genetic disruption of MXD4 compromises survival of micrometastases, preventing their progression to macrometastases. Analyses of human brain micrometastases validate this transient adaptive state in patients. Exploiting vulnerabilities associated with the proliferative pause reveals preventive therapeutic opportunities across experimental settings, including spontaneous brain metastasis models and minimal residual disease following neurosurgical resection. In addition, patient-derived organotypic cultures confirm the feasibility of targeting this state with clinically available drugs. These findings uncover a previously unrecognized adaptive stage during metastatic colonization and identify actionable vulnerabilities to prevent brain metastasis progression and relapse.
    Keywords:  autopsies; brain metastasis; metastasis initiating cells; micrometastasis; organ colonization; perivascular niche; prevention; relapse; vascular co-option; window of opportunity
    DOI:  https://doi.org/10.1016/j.ccell.2026.09.002
  10. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2616933123
    Targeted extracellular degradation of LRP8 promotes ferroptosis in cancer cells.
    Fangzhu Zhao, Alex Inague, Trenton M Peters-Clarke, Yifei Chen, Snehal D Ganjave, Yun Zhang, Kun Miao, Zi Yao, Yan Wu, Madison K C Seto, Kevin K Leung, James A Olzmann, James A Wells.
      Tumor reliance on antioxidant defenses creates a vulnerability to ferroptosis, yet strategies to therapeutically disable these systems remain limited. Here, we identify targeted degradation of the selenium uptake receptor lipoprotein receptor-related protein 8 (LRP8) as an effective approach to decrease the abundance of the ferroptosis-protective enzyme glutathione peroxidase 4 (GPX4). Using bispecific cytokine receptor-targeting chimeras (KineTACs) that couple LRP8 to cytokine receptor internalization pathways, we selectively direct LRP8 to the lysosome for degradation. LRP8 degradation reduces the abundance of several selenoproteins, including GPX4, lowering the cellular threshold for lipid peroxidation and sensitizing cancer cells to ferroptosis. These findings establish receptor-mediated selenium uptake as a critical, targetable node in ferroptosis resistance and demonstrate that extracellular protein degradation can be leveraged to reprogram intracellular translational dependencies in cancer cells. More broadly, this work provides a framework for exploiting nutrient acquisition pathways to overcome therapy resistance.
    Keywords:  LRP8; antibody engineering; ferroptosis; targeted protein degradation
    DOI:  https://doi.org/10.1073/pnas.2616933123
  11. Nat Commun. 2026 09 02. pii: 10443. [Epub ahead of print]17(1):
    The physicochemical design, structure and permeability of the JCVI-syn3A minimal cell membrane.
    Caterina Presutti, Mert Bozoflu, Joanna Juhaniewicz-Dębińska, Lauren A Lowe, Naomi Woltinge, Arathi Das, Marc C A Stuart, Siewert J Marrink, Bert Poolman.
      Minimal cells offer a platform to uncover the fundamental physicochemical principles of cellular life. While genomes, proteomes, and metabolic networks of cells have been elucidated, the lipidome, which determines the physicochemical identity of the membrane, remains only partially characterized. Yet, the membrane is a central determinant of cellular viability, regulating solute permeability, mechanical stability, and environmental cues. Here, we investigate membranes that recapitulate the lipid composition of the minimal cell JCVI-syn3A, which is distinguished by an unusually high cholesterol content and simple composition. Combining cryo-electron microscopy, Langmuir monolayer experiments, permeability assays, and coarse-grained molecular dynamics simulations, we demonstrate that cholesterol and sphingomyelin act as dominant condensing agents that stabilize the membrane while preserving an ordered yet fluid state. These lipids enhance lipid packing and acyl-chain order, whereas cardiolipin, POPC, and DOPG counterbalance condensation by promoting fluidity and compressibility. Cholesterol-sphingomyelin interactions emerge as a key thermodynamic driver that fine-tunes membrane order, fluidity, and permeability. Remarkably, membranes containing up to 60 mol% of cholesterol remain permeable to water and physiologically relevant osmolytes at rates compatible with growth of JCVI-syn3A. Together, our results define the physicochemical principles underlying minimal cell membranes and reveal how lipid composition enables passive permeation while maintaining membrane integrity.
    DOI:  https://doi.org/10.1038/s41467-026-77359-6
  12. Sci Adv. 2026 Oct 02. 12(40): eaeh8973
    Tumor cell-intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer.
    Julia Fröse, Evelyn Chen, Charles A Whittaker, Paul Leclerc, Sean Doherty, Adam Langenbucher, Jasmine Shao, Riley D Hellinger, Daniel Goulet, Tuomas Tammela, Francisco J Sánchez-Rivera, Michael T Hemann.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic cancers but has shown limited efficacy in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). The cellular and molecular factors that influence CAR T cell therapy response remain largely unknown. By integrating modular in vivo CRISPR screens with single-cell genomics and immunocompetent orthotopic models of PDAC, we uncover oxidative and proteotoxic stress pathways as previously unknown modulators of CAR T cell therapy response. Disruption of stress regulatory genes, particularly Keap1 and Slc33a1, sensitizes PDAC tumors to CAR T cell killing in vivo. Hyperactivation of the Nrf2 pathway by genetic ablation of Keap1 or endogenous engineering of clinically observed Keap1 or Nfe2l2 mutations enhances tumor susceptibility to CAR T cell therapy. Thus, tumor-intrinsic molecular stress phenotypes can induce unexpected cell state-specific vulnerabilities to cell-based immunotherapies. These findings provide a foundation to improve efficacy of CAR T cell therapy in solid malignancies and to better stratify patients with cancer by tumor genotype.
    DOI:  https://doi.org/10.1126/sciadv.aeh8973
  13. bioRxiv. 2026 Sep 24. pii: 2026.09.01.748489. [Epub ahead of print]
    Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
    Lily A Gates, Dustin C Bagley, Konstantinos Kalyviotis, John Fadul, Tania Auchynnikava, Maria Voronkov, Jody Rosenblatt.
      During homeostasis, crowded cells with the lowest energy levels are eliminated by extrusion via Piezo1 signalling to maintain constant cell numbers. However, crowding-induced extrusion does not necessarily remove damaged or otherwise unfit cells. Here, we show that glucose or glutamine starvation triggers a rapid, regulated wave of extrusion, called starvation-induced cell extrusion (STICE), that selectively eliminates cells bearing DNA damage markers via a p53-dependent, Piezo1-independent pathway, improving monolayer fitness. Unlike non-extruding cells, which recycle contents through autophagy and lysosomal digestion, p53-activated cells instead use LC3 to drive lysosomal exocytosis, promoting extrusion signalling. By eliminating defective and transformed cells, STICE confers resistance to damage and apoptotic stimuli in the remaining monolayer. STICE thus acts as a tissue-level analogue of autophagy: rather than improving individual cells by digesting and recycling damaged components, it improves tissue fitness by eliminating substandard cells.
    DOI:  https://doi.org/10.64898/2026.09.01.748489
  14. bioRxiv. 2026 Sep 24. pii: 2026.09.23.753803. [Epub ahead of print]
    Redox activation of ATG5 licenses autophagy upon nutrient restriction.
    Sanghee Shin, Ekaterina D Korobkina, Claudia Lennicke, Nils Burger, Bingsen Zhang, Haopeng Xiao, Yaoyu Wang, Jonathan J Petrocelli, Shelley M Wei, David Wood, Yu Lei, Xiaomei Zhang, Maria C Perez-Matos, Muneeb A Sharif, Jiuchun Zhang, Helena M Cochemé, William B Mair, Edward T Chouchani.
      Dietary restriction (DR) protects against metabolic disease, extends lifespan, and is associated with remodeling of tissue reactive oxygen species (ROS). ROS control biological adaptation through reversible oxidation of protein cysteines, yet the targets of DR-initiated redox signaling are unknown. Here we generate OxiDR, a tissue-resolved atlas of the cysteine redox proteome that quantifies oxidation state under DR. Rather than oxidizing the proteome broadly, DR selectively targets a high-amplitude set of cysteines in a tissue-specific manner, allowing systematic classification of biological processes subject to DR-mediated redox regulation. Among the cysteines most highly oxidized upon DR is Cys19 of the core autophagy protein ATG5. We show oxidation of Cys19 is required for ATG5-mediated autophagosome formation and for autophagy triggered by nutrient restriction in human cells and mice. Reversible oxidation of this cysteine promotes ATG5 binding to ATG10, thus forming the ATG5-ATG12 conjugate that lipidates LC3B/ATG8 and matures the autophagosome. In mice, loss of this redox switch prevents effective initiation of autophagy upon nutrient restriction, resulting in gross tissue pathology and rapid onset of mortality. The autophagic response to nutrient restriction is thus gated by oxidation of a single cysteine.
    DOI:  https://doi.org/10.64898/2026.09.23.753803
  15. Prog Biophys Mol Biol. 2026 Sep 28. pii: S0079-6107(26)00073-8. [Epub ahead of print]202 101956
    Biophysical and molecular mechanisms of lysosomal mechanoresilience: Membrane tension, TMEM63A, and cellular injury.
    Rabab S Hamad, Attalla F El-Kott, Sally Negm, Mohammed A AlShehri, Waleed Eltantawy, Elsayed A Elmorsy, Ebtehal M Abdel-Aal, Eman Hamza, Sameh Saber.
      Lysosomal membrane failure contributes to cellular injury by disrupting degradation, metabolism, immune signaling, and compartmental integrity, yet the physical principles that determine whether a mechanically loaded lysosome adapts or ruptures remain incompletely resolved. This review integrates biophysical and molecular evidence to examine lysosomal membrane tension as an organelle-state variable and TMEM63A as an emerging determinant of lysosomal mechanoresilience. We distinguish membrane tension from hydrostatic and osmotic pressure, organelle volume, membrane permeabilization, and rupture, and evaluate how surface-area-to-volume constraints, luminal solute accumulation, ion and water flux, membrane potential, lipid composition, and force-from-lipid gating shape mechanical failure thresholds. The strongest evidence comes from Drosophila TMEM63 and mouse TMEM63A lysosomal mechanosensitivity and macrophage models in which TMEM63A-dependent cation efflux lowers acute membrane tension and rupture susceptibility. Together, these findings support a pressure-relief model coupling mechanically activated conductance to lysosomal membrane stability. Evidence from lysosome-related organelles, lipid scrambling, myelination, infection, and pressure-sensitive mTORC1-TFEB/TFE3 signaling broadens the mechanistic scope without establishing a universal TMEM63A-dependent pathway. Accordingly, TMEM63A is best viewed as a system- and condition-dependent regulator of acute lysosomal mechanical vulnerability, not a general lysosomal controller or validated therapeutic target. Importantly, TMEM63A-linked disease phenotypes in humans and Tmem63a-deficient mice have not been causally linked to impaired lysosomal mechanoresilience, and the macrophage pressure-relief mechanism remains unvalidated in vivo. Resolving these uncertainties will require simultaneous, time-resolved measurements of tension, geometry, ion composition, membrane potential, permeability, and repair, combined with compartment-specific localization and rescue using wild-type, pore-defective, localization-defective, and disease-associated variants.
    Keywords:  Lysosomal membrane tension; Lysosomal rupture; Mechanosensitive ion channels; Membrane biophysics; Organelle mechanobiology; TMEM63A
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.101956
  16. Cell Rep. 2026 Oct 01. pii: S2211-1247(26)01167-8. [Epub ahead of print] 118088
    An extramedullary bone model of metastatic dormancy reveals an increased rate of metastatic reactivation upon distant insults.
    Stefania Di Blasio, Tatiana Rizou, Laurie J Gay, Nicolas Rabas, Xuanxuan Fan, Xing-Yu Liu, Victoria L Bridgeman, Ernesto Rodriguez, Probir Chakravarty, Thomas Snoeks, Adam Karoutas, Felipe S Rodrigues, Elodie Montaudon, Cristina Lo Celso, Elisabetta Marangoni, Dominique Bonnet, Bin-Zhi Qian, Ander Abarrategi, Ilaria Malanchi.
      Bone metastatic relapse can emerge years after cancer diagnosis, driven by the reactivation of disseminated tumor cells (DTCs) that remain dormant in secondary organs. This behavior is controlled by the tissue microenvironment. We developed a tuneable, skeletal progenitor-based engineered extramedullary (EM) bone model in mice that closely mimics endogenous bone and induces dormancy in metastatic breast cancer cells. Within EM bone, cancer cells remained quiescent, with occasional transient proliferative episodes. Because the model integrates with host vasculature and permits controlled release of specific factors, it enables investigation of systemic influences on dormancy. Systemic inflammation, which increases bone marrow cell production, raised the proliferative fraction of dormant cells in EM bone and increased metastatic incidence in endogenous bone. We also identified high-mobility group box 2 (HMGB2) as a factor that promotes overt metastasis and is present in human bone metastases. Therefore, EM bone represents a powerful platform for studying metastatic dormancy.
    Keywords:  CP: cancer; bioengineered extramedullary bone; bone metastasis; breast cancer; dormancy; emergency granulopoiesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.118088
  17. bioRxiv. 2026 Sep 27. pii: 2026.09.25.754490. [Epub ahead of print]
    Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx.
    Sangwoo Park, Cassidy Ho, Alexandra N Wolff, Yueyang Fan, Amanda A Bouffard, Justin Paek, Adele Mucci, Trisha R Berger, Matthew J Paszek, Marcela V Maus.
      The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.
    DOI:  https://doi.org/10.64898/2026.09.25.754490
  18. Cancer Res. 2026 Sep 30. OF1-OF17
    Exercise Modulates Microbial Metabolites and Induces Stromal Remodeling in Pancreatic Cancer.
    Sumedha Pareek, Robin D Wright, Riccardo Ballarò, Cayla Xue, Thais F Bartelli, Vidhi Chandra, Le Li, Justina Ortiz, Truong Lam, Hetal Patel, Jonghae Lee, Pradeep Shrestha, Hannah Savage, Olivereen Le Roux, Haoyue Liu, Tamara Vallejo-Schmidt, Ryan De Maleki, Vasanta Putluri, Nagireddy Putluri, Joseph F Petrosino, Jared K Burks, Javier A Gomez, Jlenia Guarnerio, Matthew H G Katz, An Ngo-Huang, Laura R Prakash, Nathan H Parker, Maria Q B Petzel, Lin Tan, Seyda Baydogan, Florencia McAllister, Keri L Schadler.
      Exercise induces a variety of changes in the tumor microenvironment, with beneficial effects in several tumor types. However, a better understanding of the clinical effects of exercise and mediating mechanisms is needed to maximize the utility of exercise for patients. In this study, we analyzed tumors from patients with pancreatic ductal adenocarcinoma (PDAC) in the PancFit trial and identified an exercise-induced reduction in cells expressing α-smooth muscle actin (αSMA). Interrogation of changes in tumor stromal composition with exercise in a murine PDAC model revealed a microbially influenced reduction in αSMA+ cells and Il6-expressing inflammatory cancer-associated fibroblasts (iCAF). Cholic acid, a microbial bile acid, was increased in both patients and murine models with exercise, as a potential mediator of exercise-induced reduction in iCAFs. Consistent with these findings, patients that exercised more also exhibited fewer iCAFs and lower tumor IL6 expression, supporting a stromal remodeling effect of physical activity. In summary, this study demonstrates that the antitumor effect of exercise includes stromal remodeling, which is affected by microbial metabolites.
    SIGNIFICANCE: Exercise-induced changes in cancer associated fibroblasts vary with microbiome composition, which may explain the heterogeneity in tumor responses to exercise and could guide future exercise trials in cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5143
  19. Cancer Res. 2026 Oct 02.
    Targeting Distinct Cell Cycle Nodes Overcomes RAS Inhibitor Resistance.
    Vishnu Kumarasamy, Jianxin Wang, Edwin H Yau, Ethan V Abel, Agnieszka K Witkiewicz, Erik S Knudsen.
      Activating mutations in KRAS drive pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Although mutant-selective KRAS inhibitors and pan-RAS inhibitors provide clinical benefits, the development of resistance limits durable responses. Here, transcriptomic and proteomic analyses revealed that, despite effective suppression of mutant KRAS signaling, resistant cells sustain cell cycle progression. Distinct orthogonal mitogenic pathways were engaged in a context-dependent manner to bypass KRAS inhibition. While these pathways could be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation was uncoupled from RAS signaling. Combinatorial drug screens and genome-wide CRISPR-Cas9 screens showed that perturbing cell cycle nodes via targeting cyclin dependent kinases CDK4/6 and CDK2 restored sensitivity to KRAS/RAS inhibitors. Co-targeting CDK4/6 induced G1 arrest and suppressed E2F-regulated proteins across all resistant models. In contrast, co-targeting CDK2 exerted a broader effect by impairing DNA replication, inducing G2 arrest, preventing mitotic entry, and yielding a more durable cytostatic response that delayed cellular outgrowth after drug withdrawal. Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yielded durable tumor control in vivo in xenografts derived from models with acquired resistance. In conclusion, these findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1315
  20. J Lipid Atheroscler. 2026 Sep;15(3): 411-444
    The Phospholipase A2 Superfamily in Health and Disease: From Lipid Signaling to Inflammation, Cancer, and Neurodegeneration.
    Mohammad Mamun Sikder, Sanzida Akter Labony.
      The phospholipase A2 (PLA2) superfamily comprises more than 50 enzymes that differ markedly in structure, catalytic mechanisms, and biological functions. Although all members share the ability to cleave acyl chains from membrane glycerophospholipids, many PLA2 enzymes catalyze additional reactions that influence membrane composition, lipid signaling, and cellular homeostasis. Through these activities, PLA2 enzymes contribute to the generation of free fatty acids, lysophospholipids, and downstream lipid mediators and participate in a wide range of physiological processes. Dysregulation of PLA2 activity has been associated with numerous pathological conditions, including inflammation, cancer, metabolic dysfunction, neurodegeneration, and tissue injury. This review summarizes the major PLA2 families, outlines their structural and biochemical features, and highlights emerging insights into their roles in health and disease.
    Keywords:  Cancer; Enzyme; Glycerophospholipids; Inflammation; Phospholipase A2; Signaling
    DOI:  https://doi.org/10.12997/jla.2026.15.3.411
  21. Drug Discov Ther. 2026 Sep 25.
    Daraxonrasib: The first-in-class RAS(ON) multi-selective inhibitor approved for treatment of metastatic pancreatic adenocarcinoma.
    Yueyi Sun, Chen Pang, Jianjun Gao.
      Advanced pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with limited benefits from conventional chemotherapy. Daraxonrasib is an oral, noncovalent RAS(ON) multi-selective inhibitor that forms a ternary complex with cyclophilin A and GTP-bound RAS, blocking downstream signaling across multiple mutant and wild-type RAS proteins. On August 26, 2026, the US Food and Drug Administration approved daraxonrasib for adults with metastatic pancreatic adenocarcinoma previously treated with systemic therapy or ineligible for multiagent systemic therapy, without a mutation-specific restriction. In the randomized phase III RASolute 302 trial involving 500 previously treated patients with a good performance status, daraxonrasib improved median overall survival from 6.7 to 13.2 months (hazard ratio, 0.40) and progression-free survival from 3.6 to 7.2 months in the overall randomized population. Grade 3 or higher treatment-related adverse events were less frequent with daraxonrasib than chemotherapy (43.6% versus 57.5%), although one treatment-related death from pneumonitis occurred. Common toxicities included rash, diarrhea, and stomatitis. Limited follow-up and small non-G12 subgroups warrant caution regarding the generalizability of that trial's results. Acquired resistance, frequently involving RAS pathway reactivation, remains an important challenge. Ongoing studies are evaluating earlier treatment settings and combination strategies, while long-term safety and outcomes in patients with a poorer performance status require further investigation.
    Keywords:  RAS; RASolute 302; daraxonrasib; pancreatic ductal adenocarcinoma; pneumonitis
    DOI:  https://doi.org/10.5582/ddt.2026.01067
  22. Cell Chem Biol. 2026 Sep 28. pii: S2451-9456(26)00327-2. [Epub ahead of print]
    Curved adhesions resist disruption by high-affinity αv-integrin inhibitors.
    Christina E Lee, Judith Martinez, Anna Amine, Wei Zhang, Chih-Hao Lu, Xingyuan Zhang, He You, Ching-Ting Tsai, Melissa L Nakamoto, Bianxiao Cui.
      Integrins are transmembrane adhesion receptors and major therapeutic targets in cancer and fibrotic diseases. High-affinity αv-integrin inhibitors, including cilengitide and MK-0429, were developed to block integrin-dependent cell adhesions. These inhibitors have been shown to disrupt integrin-mediated focal adhesions on flat, ligand-coated surfaces. Here, we demonstrate that these inhibitors are ineffective against curved adhesions, a class of integrin-mediated adhesion structures that assemble in response to membrane curvature. We find that, unlike focal adhesions, curved adhesions form under low mechanical tension, rendering them resistant to these inhibitors that act by blocking force transmission. As a result, these inhibitors also do not prevent cancer cell invasion into soft, fibrous three-dimensional extracellular matrices, a process that depends on curved adhesions. These findings expose a limitation of current integrin-targeting strategies and may help explain why some inhibitors have underperformed in clinical trials.
    Keywords:  cancer biology; cell adhesions; cell migration; curved adhesions; focal adhesions; integrins; mechanobiology; membrane biophysics; membrane curvature; nanofabrication; small-molecule inhibitors
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.017
  23. Nat Genet. 2026 Sep 30.
    Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance.
    Nicolas Mathey-Andrews, Carrie L Rodriguez, Bing Shui, Agata L Patriotis, William M Rideout, Victor Z Chen, Ileana Murazzi, Phaedra Ghazi, Milton R Cornwall-Brady, Manyuan Liu, Morgan G Heileman, Marianna Trakala, Carla P Concepcion-Crisol, Dian Yang, Tyler Jacks.
      Primary and acquired resistance to targeted therapy represent significant challenges to durable treatment responses in oncology. In lung adenocarcinoma, KRAS inhibitors are hampered by incomplete clinical responses and acquired resistance. Here we treated genetically engineered mouse models of Kras-driven lung adenocarcinoma with KRAS inhibitors to model these conditions. Initial treatment response was rapid but incomplete, with residual tumor burden transcriptionally resembling alveolar epithelial cells. With continued treatment, we invariably observed genetic Kras amplification as a resistance mechanism. To model oncogene-independent resistance, we used functional CRISPR approaches to promote squamous lineage transformation. We found that ∆Np63 was sufficient to transform alveolar organoids to a squamous state in vitro, conferring insensitivity to KRAS inhibition. In vivo, Nkx2-1 loss and/or ectopic Sox2 expression poised tumors for squamous lineage commitment. Squamous-transformed tumors did not exhibit evidence of KRAS/MAPK reactivation, underscoring the role for lineage transcription factors and histologic transformation in mediating KRAS independence.
    DOI:  https://doi.org/10.1038/s41588-026-02768-8
  24. Nat Genet. 2026 Sep 30.
    ArchMap is a web-based platform for reference-based analysis of single-cell datasets.
    Mohammad Lotfollahi, Chelsea Bright, Ronald Skorobogat, Mohammad Moghareh Dehkordi, Xavier George, Simon Richter, Vladimir A Shitov, Aleksandra Topalova, Helena Melcher, Noah Nussbaumer, Annika Fomm, Malte D Luecken, Fabian J Theis.
      Leveraging single-cell reference atlases to analyze new data has brought about a paradigm shift in single-cell data science akin to the first reference genome in genomics. However, methods for performing this mapping require computational expertise and, oftentimes, considerable compute power, limiting access for researchers who may benefit the most. Here ArchMap, a no-code query-to-reference mapping tool, removes this barrier by providing all-in-one automated mapping, cell-type annotation and collaborative features to analyze single-cell datasets from a wide range of integrated, often published, reference atlases and allows the extension of atlases with the growing Human Cell Atlas and related efforts. This paves the way for a democratization of reference mapping capabilities.
    DOI:  https://doi.org/10.1038/s41588-026-02756-y
  25. bioRxiv. 2026 Sep 23. pii: 2026.09.22.753675. [Epub ahead of print]
    Mouse lymph node colonization models predict human tumor metastasis in melanoma.
    Brendan K Ball, Reem Al-Humadi, Sabrina Zdravkovic, Ilayda Ilerten, Brooks A Benard, Brooke E Howitt, Andrew J Gentles.
      Aggressive tumor progression and distant metastases of cancers such as cutaneous melanoma are thought to be preceded by regional lymph node (LN) infiltration. Previous mouse studies have selectively enriched for tumor cells with enhanced LN migratory capacity but the mechanistic biology underpinning this proclivity has not been directly linked to human outcomes. Likewise, the exact role LN colonization plays in distant metastasis in humans remains unclear. To translate and conserve findings from mouse models to humans, we used a computational framework termed Translatable Components Regression (TransComp-R) to integrate mouse LN tumor samples with human primary and metastatic tumors. We identified transcriptional programs of early- and late-stage mouse tumor generations that stratified primary and metastatic tumors from patients with melanoma. These transcriptional programs associated with immune function, cell cycle checkpoints, and DNA-to-protein biosynthesis pathways. We then employed EcoTyper and identified six distinct melanoma-specific cellular communities (ecotypes) comprising co-occurring cell states. Of these six melanoma ecotypes, we identified a community strongly associated with primary tumor cells, while the other five represented a spectrum of metastatic tumor microenvironments with increased adverse outcomes. These ecotypes and their significantly expressed genes may contribute to the tumor-immune microenvironment that facilitates LN colonization in melanoma. We further validated the physical co-localization of these melanoma ecotypes using spatial transcriptomics. Our integration of pre-clinical models with human data reveals potential biological pathways and transcriptomic signatures for future investigation and supports the utility of mouse models in studying cancer metastasis.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.09.22.753675
  26. Adv Sci (Weinh). 2026 Sep 27. e77926
    Real-Time Monitoring of Mass and Mechanical Properties in Single Cells and Multicellular Spheroids.
    Ilaria Incaviglia, Giulia E M Ammirati, Sophie Herzog, Tommy Krug, Nico Strohmeyer, Miguel Camacho Rufino, Matthias P Lutolf, David A Weitz, Daniel J Müller.
      Cell state, growth, and mechanics are tightly connected properties underpinned by fundamental biological processes. Yet methods to quantify them simultaneously under physiologically relevant conditions, at resolutions sufficient to follow (sub)cellular processes, are still lacking. In particular, the correlation between cell state, mass, and mechanical properties during dynamic processes such as growth, differentiation, development, and disease remains poorly understood. Here, we develop experimental and theoretical approaches based on photothermally actuated microcantilevers integrated with optical microscopy to simultaneously monitor the morphology, mass, and quality (Q)-factor of single mammalian cells and larger cellular systems under culture conditions, with millisecond time resolution. We find that the Q-factor, a measure of mechanical energy dissipation, mirrors the mechanical properties of the cell, with the cytoplasm dominating as the largest and softest compartment. Our method reveals how cellular mechanical properties correlate with mass and depend on cell type, state, and growth. Applied to human spheroids, it further monitors how larger cellular systems regulate mechanical properties during development. Together, these measurements quantify mechanobiological parameters that have so far remained inaccessible, opening the way to a more complete characterization of how cellular systems regulate mechanics during fundamental processes of life.
    Keywords:  cancer; cell mass; cell mechanics; cell state; human fibroblasts; human spheroids; mechanobiology; microcantilever; mouse fibroblasts; quality‐factor
    DOI:  https://doi.org/10.1002/advs.77926
  27. EMBO J. 2026 Oct 02.
    Cellular senescence: six decades of discovery and reinvention.
    Myrthe Klaver, Lotte Sophie Steeneken, Naomi Veeningen, Abdullah Altulea, Marco Demaria.
      Cellular senescence has undergone a remarkable conceptual evolution since its discovery in 1961. Initially described by Hayflick and Moorhead as the finite proliferative lifespan of cultured human cells, senescence was first viewed as a consequence of cellular aging. The identification of telomere shortening, senescence biomarkers, and oncogene- and damage-induced senescence subsequently established its molecular basis and role as a tumor-suppressive stress response. The discovery of the senescence-associated secretory phenotype (SASP) further transformed the field by revealing that senescent cells actively communicate with and remodel their tissue environment. Genetic mouse models later demonstrated causal roles for senescent cells in tissue repair, aging, and age-related disease, while senotherapeutics established senescence as a therapeutic target. Here, we trace the major conceptual transitions that shaped the field, from replicative endpoint to stress-response program, regulator of tissue homeostasis, driver of chronic pathology, and clinically actionable process. We discuss the discoveries, controversies, and technological advances underlying these transitions and how emerging single-cell technologies, precision biomarkers, and targeted interventions are shaping the next era of senescence research.
    DOI:  https://doi.org/10.1038/s44318-026-00922-w
  28. Nature. 2026 Sep 30.
    A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation.
    Alessandra Esposito, Ibrahim Bayramoglu, Chiara Varriale, Maria Pia Cavaliere, Maria Elsa Brunetti, Rossella Agostinis, Rachel M Jansen, Dan A Tudorica, Yongjia Duan, Martina Spacci, Alessia Calcagnì, Carolin D Strobl, Verena Passerini, Fabrizio Andreone, Jlenia Monfregola, Julia Richter, Francesca Sacco, Wolfram Klapper, Oliver Weigert, Andrea Ballabio, Roberto Zoncu, James H Hurley, Joern Dengjel, Gennaro Napolitano.
      Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN-FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3. Yet how FLCN:FNIP activity is regulated has remained unclear. Here we identify a nutrient-independent lysosomal signalling pathway that regulates FLCN through v-ATPase-driven recruitment of TBK1 or ULK1 (TBK1/ULK1) to lysosomes, via the TAX1BP1 adaptor. This enables TBK1/ULK1-mediated FNIP1 phosphorylation at S296, resulting in inhibition of FLCN and nuclear translocation of TFEB. Recurrent ATP6V1B2 v-ATPase mutations, found in patients with follicular lymphoma, constitutively activate this pathway, leading to hyperactivation of TFEB and follicular lymphoma proliferation. Our work uncovers a lysosomal signalling pathway that is critical for lysosomal adaptation and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-026-11093-3
  29. ACS Chem Biol. 2026 Sep 29.
    On the Inhibition of Lipid Peroxidation and Ferroptosis by Fatty Acids.
    Melodie Mallais, Krystina Szylo, Leslie Magtanong, Mikhail S Shchepinov, Scott J Dixon, Derek A Pratt.
      Most inhibitors of lipid peroxidation (LPO) and associated ferroptosis are small molecules that trap LPO-propagating radicals. Among the handful of other inhibitors are select fatty acids: monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids substituted with deuterium atoms at their reactive bis-allylic positions (D-PUFAs), which render them significantly less reactive to LPO-propagating radicals. To probe whether the simple replacement of oxidizable PUFAs with non-oxidizable FAs is a general strategy for ferroptosis suppression, we prepared derivatives of representative PUFAs-linoleic acid (LA) and arachidonic acid (AA)-with cyclopropane rings in place of their unsaturations (CP-PUFAs). Cyclopropanation was predicted to boost the strength of the neighboring C-H bonds by ∼20 kcal/mol and increase the barrier to reaction with peroxyl radicals by ∼104-fold while preserving their cis geometry. CP-PUFAs suppressed ferroptosis induced by erastin2 in HT-1080 cells and RSL3 in HEK-293 cells, similarly to D-PUFAs and MUFAs. Palmitate, a representative endogenous saturated FA, did not suppress ferroptosis. Whereas d6-AA was more effective than d2-LA, the opposite was true of the CP-PUFAs, with CP4-AA possessing only modest activity while CP2-LA was comparable to the D-PUFAs. Lipidomics provides evidence for more extensive lipid remodeling upon treatment with CP2-LA relative to CP4-AA, with PUFAs being enriched in triacylglycerols at the expense of the diacylglycerols used for phospholipid synthesis. Overall, these results suggest that replacement of oxidizable PUFAs with non-oxidizable FAs is a general strategy to suppress ferroptosis-provided that the non-oxidizable FA can be utilized by the biosynthetic machinery and is not lipotoxic at concentrations necessary for protection.
    DOI:  https://doi.org/10.1021/acschembio.6c00583
  30. Biol Chem. 2026 Sep 29.
    Sequestosome 1 (SQSTM1/p62) at the nexus of genome integrity maintenance, proteostasis regulation and organellar homeostasis.
    Celina Hirschelmann, Prince Saforo Amponsah.
      Sequestosome 1 (SQSTM1 or p62) is a multi-domain protein that functions as a scaffold for aggregating proteins into cytoplasmic inclusions and mediating their turnover via selective autophagy. However, p62 is more than an autophagy scaffold or adaptor protein; it's linked with endo/exosomal protein trafficking and the ubiquitin proteasome system and, through its interactions with many different proteins, plays important roles in regulating cell signaling events (e.g., oxidative stress response). While its core functions are linked to proteostasis maintenance, p62 is also involved in proteostasis-independent mechanisms. In this review, we highlight the well-established role of p62 in selective autophagy in mammalian cells and harmonize known and emerging p62 functions under three main themes: proteostasis regulation, genomic integrity maintenance, and organellar homeostasis. We highlight some open questions on the potentially pivotal role of p62 in bridging these themes, which we believe would herald the next decade of research involving this versatile protein.
    Keywords:  aneuploidy; genomic integrity; mitochondria; organellar homeostasis; proteostasis; sequestosome 1 (SQSTM1/p62)
    DOI:  https://doi.org/10.1515/hsz-2026-0146
  31. Sci Immunol. 2026 Oct 02. 11(124): eaeb9068
    Multiomic analysis of malignant ascites defines RORC-expressing dendritic cells at sites of metastasis.
    Steven M Blum, Thomas L Chan, Neal P Smith, Courtney Ambrose, Katherine H Xu, Alice Tirard, Nandini Samanta, Sidney Martin, Roya Best, Elizabeth Tuttle, Christopher T Stueber, Yuhui Song, Vaishnavi R Yalala, Haley Barnes, Sean T Bannon, Chloe Simms, Benjamin Y Arnold, Mushriq Al-Jazrawe, Joseph J Zhao, Kamil Slowikowski, Jessica Tantivit, Kasidet Manakongtreecheep, Lukas M Altenburger, Simon Knott, Matthew R Strickland, Michael G Drage, Linda T Nieman, Jesse S Boehm, Raghav Sundar, Gary Reynolds, Samuel J Klempner, Alexandra-Chloé Villani.
      Malignant ascites is caused by the peritoneal dissemination of cancer and has a poor prognosis. Here, we performed multiomic analyses on ascites samples from patients with cancer and identified RORC-expressing dendritic cells (RORC DCs) enriched in malignant ascites. RORC DCs expressed PIGR and were transcriptionally similar to murine RORγt+ DCs/Thetis cells implicated in immune tolerance. We devised a high-purity sorting strategy to enable in vitro experiments with patient-derived RORC DCs, which indicated that these cells were phenotypically stable and stimulated T cell proliferation while attenuating IFNG expression. Multiplexed immunofluorescence identified RORC DCs in primary tumors and demonstrated their enrichment in regional lymph node metastases. These results associate human RORC DCs with advanced malignancies and suggest a role for these cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb9068
  32. Sci Adv. 2026 Oct 02. 12(40): eaei2831
    Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress.
    Nancy T Santiappillai, Andrew Cho, Georg Verch, Ana C Codo, Achuth Nair, Ya-Ting Wang, Allie Lipshutz, Celia Martínez de la Torre, Eric Minwei Liu, Marjan Berishaj, Alissa J Trzeciak, Zhaoquan Wang, Michelle Saoi, Waleska Saitz Rojas, Justin R Cross, Ed Reznik, Justin S A Perry, Kayvan R Keshari.
      Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aei2831
  33. Cell. 2026 Sep 29. pii: S0092-8674(26)01081-0. [Epub ahead of print]
    Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer.
    Yumeng Hu, Gaoyuan Lv, Hao Yuan, Zhijun Zhou, Shaobo Zhang, Yuxin Ye, Qun Chen, Yang Cai, Jingxuan Yang, Yuqing Zhang, Chao Xu, Wenyi Luo, Michael S Bronze, Courtney W Houchen, Yi-Ping Li, Jingyong Xu, Yuanyuan Zhang, Mingyang Liu, Min Li.
      Cachexia is a major cause of morbidity in pancreatic cancer, but the cellular circuitry linking tumor progression to systemic wasting remains incompletely understood. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry, bulk transcriptomics, and functional studies across human non-cachexia, pre-cachexia, and cachexia samples, together with mouse models, we define a cachexia-associated microenvironmental niche composed of SEMA4A+ tumor cells, AQP9+ macrophages, and LOXL2+ cancer-associated fibroblasts. Mechanistically, SEMA4A-associated signaling promotes bone morphogenetic protein-2 (BMP2)-dependent acquisition of an AQP9-associated macrophage phenotype, and macrophage-derived CXCL8 activates LOXL2+ fibroblasts. LOXL2+ fibroblasts reciprocally enhance tumor cell FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Spatial analyses demonstrate progressive enrichment of this niche with cachexia severity and association with postoperative development of cachexia in previously non-cachectic patients. These findings provide a framework linking local tumor ecosystem dynamics to cachexia progression.
    Keywords:  anorexia; cancer-associated fibroblasts; early detection; extracellular vesicles; metabolic dysfunction; multi-omics; muscle wasting; tumor microenvironment; tumor-associated macrophages; weight loss
    DOI:  https://doi.org/10.1016/j.cell.2026.09.012
  34. bioRxiv. 2026 Sep 25. pii: 2026.09.21.753167. [Epub ahead of print]
    Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer.
    Joshua Schoenfeld, Jahi Noel, Christopher McGinnis, Chenlian Fu, Brinda Alagesan, Eduardo Hernandez, Justin Jee, Nikolaus Schultz, Quaid Morris, Scott Lowe, Suzanne Cloonan, John Connolly, Ronan Chaligne, David Kelsen, Kenneth Yu, William Zhang, Eileen OReilly, Ansuman Satpathy, Tomas Ganz, Santosha Vardhana.
      Systemic iron sequestration occurs frequently in cancer due to inflammation-driven expression of the iron-regulatory hormone hepcidin. The impact of systemic iron availability on tumoral immunity is unclear. Here, we show that elevated serum hepcidin is associated with reduced survival and decreased intratumoral CD8+ T cells in patients with pancreas cancer. While hepcidin is not induced in murine tumor models, administration of a hepcidin mimetic phenocopies the T-cell-depleted tumor microenvironment seen in patients. Mechanistically, chronic antigen-driven mitochondrial dysfunction disrupts iron metabolism and selectively depletes high avidity CD8+ T cells during iron restriction. These findings establish a direct link between hepcidin-mediated iron sequestration and tumoral immunity and nominate systemic iron dysregulation as a therapeutic target to enhance anti-tumoral CD8+ T cell responses.
    DOI:  https://doi.org/10.64898/2026.09.21.753167
  35. Nat Methods. 2026 Sep 30.
    CytoVI: deep generative modeling of antibody-based single cell data.
    Florian Ingelfinger, Nathan Levy, Can Ergen, Artemy Bakulin, Alexander Becker, Pierre Boyeau, Martin Kim, Diana Ditz, Jan Dirks, Jonas Maaskola, Tobias Wertheimer, Robert Zeiser, Corinne C Widmer, Ido Amit, Nir Yosef.
      Antibody-based single-cell technologies, such as flow cytometry, mass cytometry and CITE-seq, have become widely used in clinical diagnostics and basic research; however, their analysis is complicated by technical noise, batch effects, platform differences and restricted antibody panels. Here we present CytoVI, a probabilistic generative model for statistically rigorous unified analysis of antibody-based single-cell data. CytoVI generates informative cell embeddings, imputes missing measurements, performs differential protein expression testing and automates annotation of cells in a single probabilistic model. We applied CytoVI to build an integrated B cell maturation atlas spanning 350 proteins and identified proteins associated with immunoglobulin class-switching. In a cohort of patients with B cell non-Hodgkin lymphoma profiled by flow cytometry and CITE-seq, CytoVI uncovered disease-associated T cell states. CytoVI is available as open-source software at scvi-tools.org .
    DOI:  https://doi.org/10.1038/s41592-026-03224-5
  36. Eur Biophys J. 2026 Sep 30.
    Electric-field manipulation of giant vesicles: new frontiers in membrane electromechanics.
    Rumiana Dimova, Elias Sabri.
      Giant unilamellar vesicles (GUVs) are a powerful model system whose response to electric fields constitutes a strategy to directly assess membrane material properties. In the last few years, the field has advanced in both conceptual scope and experimental precision. Electric-field manipulation of GUVs remains a versatile platform for extracting membrane mechanical, electrical, and rheological properties with single-vesicle resolution, while increasingly extending from a diagnostic tool into an actuation mechanism. Here, we summarize classical electrodeformation and electroporation methodologies and review recent developments that push these approaches toward greater biological realism, including compound vesicles as nucleate-cell mimics, resting-membrane-potential- and ion-dependent poration, phase-transition electromechanics, and cytoskeleton-loaded, field-responsive membranes. We also discuss how electric fields are combined with other stimuli, such as light and biochemical cues, and repurposed to drive active, motile vesicle assemblies and to fabricate tailored lipid architectures at high throughput. We further highlight theoretical work on electromechanical coupling, membrane charging dynamics, and vesicle shape landscapes under electric stress. We close by outlining remaining challenges, from reproducibility across preparation protocols to bridging model membranes and living cells, and future opportunities for automated, high-throughput, and multimodal electromechanical studies of biomimetic membranes.
    Keywords:  Electrodeformation; Electromechanical coupling; Electroporation; Giant unilamellar vesicles; Membrane mechanics; Photoswitchable lipids
    DOI:  https://doi.org/10.1007/s00249-026-01869-w
  37. Sci Transl Med. 2026 Sep 30. 18(869): eaea4608
    FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non-small cell lung cancer.
    Silvia Coma, Monica Musteanu, Cristina Caffarra Malvezzi, Ryan R Jamieson, Enrico Patrucco, Alessia Mira, Julien Dilly, Ziyue Li, Ana Fernández-Rodríguez, Alejandra López-García, Andrew J Aguirre, Mariano Barbacid, Chiara Ambrogio, Jonathan A Pachter.
      KRAS G12C (Gly12→Cys) inhibitors (G12Cis) have improved outcomes for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), but their clinical benefit is limited by the emergence of resistance mechanisms. Here, we demonstrate that combining the RAF/MEK clamp avutometinib and the focal adhesion kinase (FAK) inhibitor defactinib with a G12Ci enhanced antitumor activity by deepening mitogen-activated protein kinase (MAPK) pathway suppression and simultaneously inhibiting adaptive resistance pathways induced by G12Ci and avutometinib treatment, including FAK and PI3K signaling. In KRAS G12C NSCLC mouse models, the triplet combination produced greater tumor growth inhibition than either sotorasib alone or the sotorasib plus avutometinib doublet. Moreover, in KRAS G12C NSCLC mouse models resistant to sotorasib, the addition of avutometinib and FAK inhibition restored sensitivity to sotorasib and increased both the depth and durability of antitumor responses. Collectively, these findings demonstrate that concurrent targeting of KRAS G12C, RAF/MEK, and FAK signaling can overcome multiple resistance mechanisms and provide a strong rationale for the clinical evaluation of sotorasib, avutometinib, and defactinib in patients with KRAS G12C-mutated NSCLC (RAMP 203; NCT05074810).
    DOI:  https://doi.org/10.1126/scitranslmed.aea4608
  38. Redox Biol. 2026 Sep 28. pii: S2213-2317(26)00417-9. [Epub ahead of print]97 104418
    The fruitfly Drosophila melanogaster as an in vivo model of ferroptosis.
    Li Zhang, Felix Schmidt, Fatih Yasar, Yasminn Akele, Bernhard Michalke, Konstantin Beckschäfer, Christoph Thiele, Eva-Maria Hanschmann, Vivek Venkataramani, Axel Methner.
      Ferroptosis is an iron-dependent form of cell death involved in cancer, ischemia-reperfusion injury, inflammation, and neurodegeneration. It can be triggered in two ways: class 1 inhibitors such as erastin block system xc-, the cystine/glutamate antiporter composed of xCT and 4F2hc/CD98, causing glutathione depletion, whereas class 2 inhibitors such as RSL3 directly inhibit glutathione peroxidase 4, causing lipid peroxidation. Ferroptotic cell death is suppressed by radical-trapping antioxidants like ferrostatin-1. We investigated the effects of erastin and RSL3 on Drosophila melanogaster lifespan, iron metabolism, and lipid composition. Erastin and RSL3 dose- and diet-dependently shortened lifespan which was rescued by ferrostatin-1. Erastin increased the Fe2+/Fe3+ ratio and reduced ferritin-bound iron, and RSL3 remodeled lipid composition consistent with lipid peroxidation. Both effects occurred only in male w1118 flies although both sexes had similarly reduced lifespans. Total glutathione was unchanged by erastin; notably, the fly GPX4 ortholog Gtpx is a non-selenocysteine, thioredoxin-dependent peroxidase. Complete Gtpx knockout caused early lethality mirroring the embryonic lethality of constitutive GPX4 knockout in mice but was not affected by ferrostatin-1. Flies also lack a clearly defined xCT ortholog. Together, these results establish male w1118 flies as a suitable in vivo ferroptosis model and point to glutathione-independent actions of erastin.
    Keywords:  Drosophila; Ferroptosis; In vivo model; Iron homeostasis
    DOI:  https://doi.org/10.1016/j.redox.2026.104418
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