bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–05–10
fifty-five papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.
  2. PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.
  3. Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.
  4. Pancreatic cancer.
  5. Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer.
  6. The immunobiology of pancreatic cancer metastasis: premetastatic niche formation, organ-specific immune landscapes, and therapeutic opportunities.
  7. Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer.
  8. Disrupted molecular glue complex drives RAS inhibitor resistance.
  9. A peritumoral microenvironment engaged by Reg-EXTL3 axis fosters nerve-cancer interactions in pancreatic ductal adenocarcinoma.
  10. Ghosts on the Membrane: Cytoskeletal Pinning Influences Nanoscale Cell Membrane Organization.
  11. LIPID MAPS: Powering discovery in lipidomics.
  12. Phosphorylation tunes p62 condensates to drive autophagic degradation of ubiquitinated proteins.
  13. C26 and CT26 colorectal cancer models exhibit divergent cachexia phenotypes, intramuscular inflammation, and protein turnover signaling.
  14. Oncogene-Mechanics Axis: KRAS G12C Confers Agility Enabling Malignant Mechano-responses to Peristalsis in Colorectal Cancer.
  15. Uncoupling of nutrient sensing and cell size control by specific defects in ceramide structure.
  16. Cancer-Associated Fibroblasts Promote Epithelial-Mesenchymal Transition and Classical to Basal Subtype Shift in Pancreatic Cancer.
  17. Whole-genome doubling drives immune evasion by silencing antigen presentation.
  18. Lipofuscin accumulation in aging and CLN1 is associated with deficient de-S-acylation, lyso-mitochondrial dysfunction, and lipid dyshomeostasis.
  19. Peroxisome-derived ether lipids regulate lysosomal exocytosis.
  20. Sarcopenia as a Marker of Immunometabolic Vulnerability in Pancreatic Ductal Adenocarcinoma.
  21. Acquired resistance to the PRMT5 inhibitor confers collateral sensitivity to MEK inhibition in MTAP-null non-small cell lung cancer.
  22. Selective Editing and Functionalization of the Mammalian Lipidome.
  23. Pancreatic cancer.
  24. FILM: Mapping organellar metabolism by mid-infrared photothermal modulated fluorescence.
  25. Unraveling autophagy-metabolism crosstalk in cancer: Molecular insights and therapeutic strategies.
  26. RHOV couples EMT-associated plasticity to cytoskeletal execution of invasion and metastasis.
  27. Do crowded phospholipid monolayers remain fluid?
  28. Reconstituted nascent adhesion condensates drive actin polymerization on supported lipid bilayers.
  29. Bioengineered systems to exploit tumor microenvironment metabolism.
  30. Implantable Microdevices for In Vivo Assessment of Chemotherapy Response in Patient Derived Organoid Orthotopic Pancreatic Cancer Models.
  31. When tau stalls the lysosome: decoupling trafficking and degradation in autophagy.
  32. TranscriptFormer: A generative cell atlas across 1.5 billion years of evolution.
  33. Novel Genetic Risk Loci for Pancreatic Ductal Adenocarcinoma Identified in a Genome-wide Study of African Ancestry Individuals.
  34. Phosphatidylserine is a component of the gradient-tracking machine in mating yeast.
  35. How membranes shape up for lipid transfer.
  36. Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
  37. A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer.
  38. Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.
  39. NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer.
  40. Decoding protein-phospholipid interaction networks in cancer: the role of acyl-chain remodeling.
  41. Foundation cell segmentation models performance on live microscopy and spatial-omics data.
  42. Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations.
  43. 25 years of chemistry that simply clicks.
  44. Chemical Mechanisms of Lipid Peroxidation.
  45. FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
  46. Protocol to determine in vitro lipid-protein interactions using liposome flotation assay.
  47. Oxidized Phosphatidylcholines Regulate Secretory Phospholipase A2 Through Membrane Nanodomain Remodeling.
  48. How CAR T cells can be shielded from prostaglandin E2 signaling to enhance their therapeutic activity.
  49. Impact of UGT1A1*28 polymorphism in patients with metastatic pancreatic ductal adenocarcinoma treated with NALIRIFOX in the NAPOLI 3 trial.
  50. Genetic mutations governing ferroptosis sensitivity and resistance: a precision approach to cancer therapy.
  51. PARP2 deficiency impairs pancreatic cancer progression by promoting genomic instability and antitumor immunity.
  52. Neutrophil-Driven Trogocytosis in PDAC Liver Metastases Restrains Immunosuppressive Macrophage Polarization and Limits Metastatic Progression.
  53. Hide-and-seek molecular navigator targets tumor cell surface thiols by programmable disulfide exchange.
  54. Fasting opens a metabolic window that favors anti-tumor immunity.
  55. Dual Pathways of Extracellular ATP Action in Cancer Cells: Purinergic Signaling-Driven Senescence and Macropinocytic ATP Internalization.
  1. bioRxiv. 2026 Apr 21. pii: 2026.04.18.719329. [Epub ahead of print]
    Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.
    Wen-Hsuan Chang, Alec J Vaughan, Addison G Stamey, Mariana Mancini, Makiko Hayashi, Runying Yang, Ryan Robb, Daniel Andrussier, Jeffrey A Klomp, Andrew M Waters, Antje Schaefer, Brian M Wolpin, Kirsten L Bryant, Adrienne D Cox, Fernando Moreira Simabuco, Kwok-Kin Wong, Andrew J Aguirre, Clint A Stalnecker, Thales Papagiannakopoulos, Channing J Der.
      The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRAS G12D -selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977 in pancreatic cancer models. RNA-sequencing analyses revealed a KEAP1 KO transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating a distinct mechanism of resistance. We then established a PDAC KEAP1-deficient (PKD) gene signature that was enriched in patients and preclinical models insensitive to KRAS inhibitor treatment. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the glutamine antagonist DRP-104 (sirpiglenastat) enhanced KRAS inhibitor suppression of pancreatic and lung tumors.
    SIGNIFICANCE: KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.
    DOI:  https://doi.org/10.64898/2026.04.18.719329
  2. Cancer Res. 2026 May 07.
    PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition.
    Xiangyu Ge, Jaffarguriqbal Singh, Wenxue Li, Cassandra S Markham, Christian Felipe Ruiz, Edward C Stites, Moitrayee Bhattacharyya, Yansheng Liu, Mandar Deepak Muzumdar.
      Despite the availability of RAS inhibitors and the dependence of >90% of pancreatic ductal adenocarcinomas (PDAC) on oncogenic KRAS mutations, resistance to KRAS inhibition remains a serious obstacle. We showed here that PI3K plays a major role in this resistance through upstream activation of wild-type RAS signaling - beyond its known KRAS effector function. The combination of proximity labeling, CRISPR screening, live-cell imaging, and functional assays revealed that PI3K orchestrates phosphoinositide-mediated GAB1 recruitment to the plasma membrane, nucleating assembly of RAS signaling complexes that activate MAPK in an EGFR/SHP2/SOS1-dependent manner. Inhibiting PI3K enhanced sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including in cells with clinically identified PIK3CA mutations. These findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven wild-type RAS activation drives resistance to KRAS inhibition, and illuminate avenues for augmenting KRAS-targeted therapies in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3625
  3. bioRxiv. 2026 Apr 23. pii: 2026.04.21.719930. [Epub ahead of print]
    Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.
    Pavel Stupakov, Golbahar Sadatrezaei, Ines Velazquez Quesada, Lillian A Boe, Chun-Hao Chen, Francesca Gaino, Efsevia Vakiani, Ihsan Ekin Demir, Boris Reva, Bojana Gligorijevic, Richard J Wong, Sylvie Deborde.
       Background: Fibrosis and tumor innervation are two features of the tumor microenvironment (TME) that contribute directly to the lethality of pancreatic ductal adenocarcinoma (PDAC), but their potential interactions have not been explored. Moreover, although it is known that activated Schwann cells (SCs) stimulate cancer cell invasion, it remains unclear how SCs are activated.
    Objective: We determined how SCs are activated in the pancreatic fibrotic microenvironment.
    Design: The correlation between physical features of the microenvironment and SC activation was assessed in human patient samples and in mice by SC c-Jun phosphorylation monitoring, atomic force microscopy and multiphoton live imaging. Several in vitro models in which forces were applied to SCs expressing a reporter for c-Jun phosphorylation and RNA-Seq analysis were used to decipher the cellular and molecular mechanisms of SC activation.
    Results: Nerves surrounded by stiff stroma present higher SC activation. Intravital imaging shows a matrix dependent SC activation. Mechanical forces on SCs induce c-Jun phosphorylation in SCs in a non-canonical manner that involves a nuclear sensing machinery with the proinflammatory enzyme Phospholipase A2.
    Conclusion: Fibrosis enhances the protumorigenic impact of innervation by activating SCs via a mechanism in which nuclear compression triggers non-canonical activation of the AP-1 transcription factor complex. Pancreatic fibrosis alone, without cancer cells, is sufficient to activate SCs, suggesting this mechanism may be common across non-malignant pancreatic diseases. Notably, SCs are more sensitive to mechanical activation than PDAC cells. These findings reveal TME interactions that may guide future microenvironment-targeted PDAC therapies.
    What is already known on this topic: The pancreatic cancer tumor microenvironment is highly innervated and fibrotic, two components of the tumor microenvironment that regulate tumorigenesis. How they impact each other is unknown. Schwann cells have emerged as a significant protumorigenic player, but the triggers of Schwann cell activation remain undefined.
    What this study adds: We establish that fibrosis induces Schwann cell activation and characterize the mechanism by which it occurs. We uncovered a mechanical mode of action that deforms nuclear membrane and activates c-Jun in Schwann cells, which contradicts the traditional view of c-Jun activation through a stimulus detected at the plasma membrane.
    How this study might affect research practice or policy: This study provides a better understanding of the biology of pancreatic ductal adenocarcinoma and supports the development of novel precision therapies that target the fibrotic microenvironment to impact the protumorigenic effect of tumor innervation.
    DOI:  https://doi.org/10.64898/2026.04.21.719930
  4. Nat Rev Dis Primers. 2026 May 07. pii: 24. [Epub ahead of print]12(1):
    Pancreatic cancer.
      
    DOI:  https://doi.org/10.1038/s41572-026-00708-8
  5. N Engl J Med. 2026 May 07. 394(18): 1790-1802
    Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer.
    RMC-6236-001 Investigators
       BACKGROUND: Current therapies for patients with pancreatic ductal adenocarcinoma (PDAC) provide modest benefit. Activating RAS mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS.
    METHODS: In this phase 1-2 study, we evaluated daraxonrasib in patients with advanced solid tumors with activating RAS mutations. Patients received 10 to 400 mg of daraxonrasib orally once daily; 300 mg was selected as the phase 3 dose. The primary end point was safety. Pharmacokinetics and antitumor activity were secondary end points. This report focuses on the 168 study patients with previously treated RAS-mutated PDAC.
    RESULTS: Among the 168 patients with PDAC who received daraxonrasib at a dose of 300 mg or less, treatment-related adverse events of any grade were reported in 96%; such events of grade 3 or higher were reported in 30%. Treatment-related adverse events that occurred in at least 10% of the patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue. In a subgroup of 26 patients with RAS G12 mutations who were treated with second-line daraxonrasib at a dose of 300 mg, an objective response to therapy was reported in 35% (95% confidence interval [CI], 17 to 56). The median duration of response was 8.2 months (95% CI, 3.8 to not evaluable), with median values of 8.5 months for progression-free survival and 13.1 months for overall survival. Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival.
    CONCLUSIONS: Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).
    DOI:  https://doi.org/10.1056/NEJMoa2505783
  6. Cancer Metastasis Rev. 2026 May 05. pii: 27. [Epub ahead of print]45(2):
    The immunobiology of pancreatic cancer metastasis: premetastatic niche formation, organ-specific immune landscapes, and therapeutic opportunities.
    Daniel R Principe.
      Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall survival and is largely refractory to standard therapies. Most patients present with locally advanced or metastatic disease, and those with early-stage tumors amenable to surgical resection face high rates of metastatic relapse. Despite the many successes of immunotherapy in other solid tumors, these approaches have shown only marginal activity in PDAC. In PDAC, metastasis occurs through a coordinated, multistep process characterized by a gradient loss of immune surveillance. This process begins with establishment of a receptive premetastatic niche, which occurs via conditioning of distant tissues by tumor-derived exosomes and the recruitment of myeloid cells, leading to extracellular matrix remodeling and local immunosuppression prior to metastatic dissemination. On arrival of metastatic cells, tissues undergo organ-specific immune editing with important implications for therapeutic vulnerability. Importantly, liver metastases maintain a profoundly immunosuppressive environment whereas lung metastases have higher immune activity. These observations challenge the prevailing assumption that insights from primary tumors are broadly applicable to metastatic disease, establishing metastatic PDAC as a distinct immunologic entity. This framework identifies unique therapeutic opportunities across the disease spectrum from early interventions targeting premetastatic niche formation to site-specific strategies for established metastatic disease.
    Keywords:  Immunotherapy resistance; Metastasis; Pancreatic ductal adenocarcinoma; Tumor immunology; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10555-026-10334-1
  7. Cancer Cell. 2026 May 07. pii: S1535-6108(26)00216-3. [Epub ahead of print]
    Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer.
    Courtney T S Kureshi, Michael J Walsh, Rakeeb Kureshi, Victoire Cardot-Ruffino, Dennis A Agardy, Lestat R Ali, James M Dougan, Li Qiang, Jiao Shen, Chong Zuo, Patrick J Lenehan, S Jennifer Wang, Eugena Chang, Joshua Remland, Lauren Brais, Thomas E Clancy, James M Cleary, Jason L Hornick, Brandon M Huffman, Joseph D Mancias, George Molina, Mark Fairweather, Jonathan A Nowak, Kimberly J Perez, Douglas A Rubinson, Sarah Slater, Ritchell van Dams, Jiping Wang, Brian M Wolpin, Lei Zhao, Katharine Barrientos, Ruslan Novosiadly, Miranda Broz, Harshabad Singh, Michael Dougan, Stephanie K Dougan.
      Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8+ T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8+ T cells or tumor cell MHC expression but instead requires IFNγ-producing CD4+ T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4+ T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4+ T cell-IFNγ axis could be efficacious in PDAC.
    Keywords:  CD4(+) T cells; CTLA-4; IFNγ; PD-1; PDAC; STING; cDC2; dendritic cells; immune checkpoint blockade; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.ccell.2026.04.005
  8. Cell. 2026 May 05. pii: S0092-8674(26)00332-6. [Epub ahead of print]
    Disrupted molecular glue complex drives RAS inhibitor resistance.
    Ben Sang, Ling Feng Ye, Zheng Fu, Yasin Pourfarjam, Antonio Cuevas-Navarro, Shijie Fan, Feng Hu, Aaliyah Washington, Diego J Rodriguez, Alberto Vides, Sumit Kar, Ethan Ahler, Kevin K Lin, Aparna Hegde, Jacqueline A M Smith, Brian M Wolpin, Salman R Punekar, Alexander I Spira, Ignacio Garrido-Laguna, David S Hong, Arvin C Dar, Rona Yaeger, Kathryn C Arbour, Piro Lito.
      Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling. Although these agents have shown clinical activity in RAS mutant cancers, resistance mechanisms remain poorly defined. Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases. Structural and functional analyses revealed that acquired mutations confer resistance by disrupting interactions essential for daraxonrasib binding to RAS, including RAS Y64 mutations, or by enhancing the RAS-RAF interaction, thereby favoring native RAS-RAF signaling, including RAS Y71 or kinase-dead/hypoactive BRAF mutations. We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.
    Keywords:  RAF; RAS; RAS inhibitor; acquired resistance; cancer; clinical resistance; daraxonrasib; molecular glues; targeted therapy; tri-complex inhibitor
    DOI:  https://doi.org/10.1016/j.cell.2026.03.031
  9. Neuron. 2026 May 07. pii: S0896-6273(26)00269-2. [Epub ahead of print]
    A peritumoral microenvironment engaged by Reg-EXTL3 axis fosters nerve-cancer interactions in pancreatic ductal adenocarcinoma.
    Shan Zhang, Fang-Yuan Dong, Shuqi Cai, Bin Zhou, Luju Jiang, Li-Peng Hu, Yu-Heng Zhu, Hui Li, Xiao-Mei Yang, Zhiwei Cai, Lin-Li Yao, Hao Wang, Hong-Fei Yao, Jun Li, Qing Li, Lei Zhu, Qin Yang, Li-Min Liu, Yan-Qiu Yu, Jun-Feng Zhang, Rong Hua, Xue-Li Zhang, Helen He Zhu, Ningning Niu, Jing Xue, Chongyi Jiang, Yong-Wei Sun, Qingjian Han, Dong-Xue Li, De-Jun Liu, Zhi-Gang Zhang, Shu-Heng Jiang.
      Tumor innervation (TIN) and perineural invasion (PNI) are well-established pathological features of pancreatic ductal adenocarcinoma (PDAC) that drive its aggressiveness and associated pain. Here, we reveal that regenerating islet-derived (Reg) proteins, secreted by peritumoral exocrine acinar cells, facilitate TIN and PNI through two paracrine mechanisms. In PDAC cells, Reg proteins drive cancer invasiveness along nerves via autocrine transforming growth factor β (TGF-β) signaling. In neurons, Reg proteins are neurotrophic and potentiate neuronal excitability, resulting in hyperinnervation and pain. Interleukin-22, primarily produced by CD4+ T cells, triggers Reg expression. Exostosin-like glycosyltransferase 3 (EXTL3) is the functional receptor for Reg proteins in both cell types. Genetic silencing of Reg or EXTL3 reduces TIN, nerve-cancer proximity, PDAC progression, and pain behavior in mice. Clinically, the Reg-EXTL3-TGF-β axis correlates with increased TIN and PNI severity, poor prognosis, and greater pain. Thus, targeting the Reg-EXTL3 axis may be an attractive strategy for mitigating neural-associated adverse consequences in PDAC.
    Keywords:  cancer neuroscience; nerve dependence; neural invasion; neural remodeling
    DOI:  https://doi.org/10.1016/j.neuron.2026.03.039
  10. Biomolecules. 2026 Apr 17. pii: 596. [Epub ahead of print]16(4):
    Ghosts on the Membrane: Cytoskeletal Pinning Influences Nanoscale Cell Membrane Organization.
    Shambhavi Pandey, Thorsten Wohland.
      The lateral organization of the plasma membrane (PM) is vital for cellular signaling, yet the specific mechanisms by which the internal cortical actin meshwork templates the organization of the external lipid leaflet remain poorly understood. While established models like the 'picket-fence' emphasize physical barriers to diffusion, recent observations of fiber-like "ghost" structures in the distribution of glycosylphosphatidylinositol-anchored proteins (GPI-APs) suggest a more intricate mode of spatial coordination. In this study, we utilize imaging total internal reflection fluorescence correlation spectroscopy (ITIR-FCS) and variable-angle TIRF to resolve whether these filamentous patterns represent genuine membrane-proximal features or optical artifacts of cytosolic transport. Our results demonstrate that these fiber-like tracks are strictly confined to the immediate PM interface and disappear as the evanescent field probes deeper into the cytosol. While the spatial distribution of GPI-APs is templated by the underlying actin meshwork, quantitative diffusion mapping shows that the lateral dynamics of the probe remains largely uniform and is not significantly modulated by these filamentous patterns. By pharmacologically perturbing the actin scaffold and membrane cholesterol, we show that this transbilayer coupling is contingent upon a cholesterol-dependent cytoskeletal pinning mechanism. These findings demonstrate a decoupling of spatial organization and molecular dynamics, providing evidence for how the actin scaffold patterns nanoscale membrane organization without imposing long-range barriers to diffusion.
    Keywords:  GPI-anchored proteins; ITIR-FCS; cholesterol; cortical actin; cytoskeletal pinning; membrane topography; plasma membrane; transbilayer coupling
    DOI:  https://doi.org/10.3390/biom16040596
  11. Sci Signal. 2026 May 05. 19(936): eaeg3389
    LIPID MAPS: Powering discovery in lipidomics.
    Lauren Cockayne, Matthew J Conroy, Chetin Baloglu, Eoin Fahy, Gerhard Hagn, Oswald Quehenberger, Aaron M Armando, Gabriele Lombardi Bendoula, Jean-Marie Galano, Ángel Sánchez-Illana, Thierry Durand, Nadja Kampschulte, Paul D Kennedy, Miguel Gijón, Hiroshi Tsugawa, Makoto Arita, Kirk Maxey, Meghan Truskowski, Ondrej Kuda, Shazia Khan, Natalie Z M Homer, Yuki Matsuzawa, Rosario Domingues, Peter J Meikle, Corey Giles, Kevin Huynh, Robert C Murphy, Zidan Wang, Yu Xia, Xue Li Guan, Kim Ekroos, Gerhard Liebisch, Alfred H Merrill, Andrea F Lopez-Clavijo, Dominic Campopiano, Craig E Wheelock, Shankar Subramaniam, Robert Andrews, Laura Goracci, Zhixu Ni, Maria Fedorova, Simon Andrews, William Griffiths, Ruth Andrew, Edward A Dennis, Valerie B O'Donnell.
      As lipidomics approaches its 25th anniversary, we explore how lipid research has matured over the years while highlighting emerging innovations that are expanding our ability to study these diverse, life-critical biomolecules. In particular, we showcase the community-driven, open-access databases, software, and educational resources made freely available through the ELIXIR Core Data Resource LIPID MAPS for the benefit of both established and new researchers.
    DOI:  https://doi.org/10.1126/scisignal.aeg3389
  12. EMBO J. 2026 May 05.
    Phosphorylation tunes p62 condensates to drive autophagic degradation of ubiquitinated proteins.
    Satoko Komatsu-Hirota, Keisuke Tabata, Yu-Shin Sou, Soichiro Kakuta, Jun-Ichi Sakamaki, Hikaru Tsuchiya, Jiachen Li, Hiroyuki Kumeta, Yuji Sakai, Yuko Fujioka, Daisuke Noshiro, Shunsuke F Shimobayashi, Tomo Kurimura, Takashi Taniguchi, Manabu Abe, Masato Koike, Hideaki Morishita, Nobuo N Noda, Masaaki Komatsu.
      p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates ("p62 bodies") that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a threshold-dependent modulator of a condensate's physical properties and promotes their rapid autophagic clearance. Phosphorylation within p62 bodies drives a transition from large, fluid droplets to compact, gel-like condensates that efficiently capture LC3-positive isolation membranes and accelerate the autophagic removal of ubiquitinated proteins. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. Homozygous p62S403E/S403E knock-in embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies. Consistently, phosphorylation-mimetic knock-in mice show similar remodeling of p62 condensates in vivo, demonstrating that this phosphorylation-driven mechanism maintains proteostasis across scales. We propose that Ser403 phosphorylation functions as a molecular switch that couples the material state of p62 condensates to their stability and serves as a central control point for p62-mediated protein degradation.
    DOI:  https://doi.org/10.1038/s44318-026-00785-1
  13. bioRxiv. 2026 Apr 24. pii: 2026.04.21.719997. [Epub ahead of print]
    C26 and CT26 colorectal cancer models exhibit divergent cachexia phenotypes, intramuscular inflammation, and protein turnover signaling.
    Xinyue Lu, Hanan Tlais, Hamood Rehman, Ashtyn N Martens, Abigail L Hartz, Vandre C Figueiredo, James F Markworth.
      Colorectal cancer (CRC) cachexia induces skeletal muscle dysfunction, impeding quality of life and worsening cancer prognosis. Multiple preclinical models, including the widely used mouse model of subcutaneous inoculation with the C26 colorectal carcinoma cell line, have been developed to study the biological mechanisms of CRC cachexia and elucidate potential new treatments. It has been proposed that a distinct cell line of the same origin, namely CT26, is relatively non-cachexic. However, studies evaluating the relative potential of C26 and CT26 cells to induce cancer cachexia in parallel have been limited. The differences in the biological mechanisms by which C26 and CT26 impact skeletal muscle mass and function have also not been fully elucidated. In the current study, we investigated the differential capacity of C26 and CT26 to induce cancer cachexia using both an in vitro cancer-muscle cell co-culture and an in vivo syngeneic mouse model. Our results show that both C26 and CT26 cells induced significant atrophy of murine C2C12 skeletal myotubes. In the mouse model, while C26 and CT26 both reduced skeletal muscle mass and fat mass, only C26 tumors led to loss of body weight and impaired skeletal muscle force output. We further show that C26 tumor-bearing mice exhibit greater muscle inflammation than CT26 tumor-bearing mice. In addition, mice bearing C26 and CT26 tumors showed differential regulation of the innate immune responses and muscle protein turnover. Overall, our data suggests that although both C26 and CT26 cells do exhibit cachexic effects, C26 cells induce greater loss in body weight, fat mass, skeletal muscle mass, and physical function via promoting chronic inflammation and deregulating protein balance of skeletal muscle.
    DOI:  https://doi.org/10.64898/2026.04.21.719997
  14. bioRxiv. 2026 May 01. pii: 2026.04.28.721453. [Epub ahead of print]
    Oncogene-Mechanics Axis: KRAS G12C Confers Agility Enabling Malignant Mechano-responses to Peristalsis in Colorectal Cancer.
    Astha Lamichhane, Vsevolod Cheburkanov, Mykyta Kizilov, Abhinav Shenoy, Audrey G Head, Vladislav Yakovlev, Shreya Artha Raghavan.
      Oncogene activity and mechanical forced individually and collective drive colorectal cancer, yet the integration of these signals is unknown. We used a patented peristalsis bioreactor to determine how oncogenic KRAS G12C mutations alter the cellular response to colonic peristalsis. Although both ehalthy intestinal cells and KRAS G12C cells sensed peristalsis via ERK phosphorylation, their mechano-responses diverged significantly. Peristalsis triggered a 9-fold enrichment of LGR5+ cancer stem cells in KRAS G12C cancer cells, an effect absent in healthy controls. Using Brillouin microscopy, we discovered that KRAS G12C induced a more agile and deformable mechano-phenotype by lowering intracellular viscosity, a state further amplified by peristalsis. This agility allowed KRAS G12C cancer cells to leverage, rather than resist peristalsis, resulting in LGR5 enrichment and malignant progression. Pharmacologic inhibition of KRAS G12C reverse the mechano-phenotype, while introducing KRAS G12C into healthy cells recapitulated it. Our findings identify a novel KRAS oncogene-mechanics axis, suggesting that targeting the cell's mechanical state could be a powerful complement to emerging KRAS-directed therapies.
    DOI:  https://doi.org/10.64898/2026.04.28.721453
  15. Biol Open. 2026 May 07. pii: bio.062633. [Epub ahead of print]
    Uncoupling of nutrient sensing and cell size control by specific defects in ceramide structure.
    José Ignacio Quesada-Márquez, Ana Serrano, María Alcaide-Gavilán, Rafael Lucena.
      Ceramides are essential structural lipids whose chemical diversity arises from variations in acyl-chain length and sphingoid-base modifications, yet how these structural features couple metabolic state to growth regulation remains unclear. In Saccharomyces cerevisiae, the TORC2-Ypk1/2 signaling axis coordinates plasma membrane homeostasis with cellular growth; however, the lipid-derived signals modulating this pathway are not fully defined. Here, we establish that the elongation of very-long-chain fatty acids (VLCFAs) specifically to C26 is a critical determinant of the nutrient-dependent regulation of TORC2 activity. Based on a molecular caliper model for acyl-chain determination, we show that the TORC2-Ypk1 axis is specifically tuned to detect the successful completion of C26-VLCFA synthesis. Disrupting VLCFA elongation (elo3▵) triggers constitutive TORC2 hyperactivation and a failure to reduce cell size in response to nutrient limitation. By expressing mammalian ceramide synthases (CerS1-S4), we demonstrate that TORC2 nutrient-sensing is specifically tuned to acyl-chain length. While CerS1, CerS3, and CerS4 restore the rapid, nutrient-induced downregulation of TORC2, CerS2 expression phenocopies the elo3▵ mutant, exhibiting a total kinetic failure to inhibit TORC2 signaling upon nutrient shift. Notably, cells producing C18 ceramides (GhLag1) maintained size control despite elevated TORC2 activity, revealing that ceramide-dependent signaling intensity and the physical execution of size regulation can be uncoupled. We further demonstrate that while sphingoid-base hydroxylation is required for the execution of size remodeling, it is dispensable for nutrient sensing; sur2▵ mutants exhibited severe size defects despite maintaining statistically normal, nutrient-responsive TORC2 signaling. Overall, our findings reveal a functional hierarchy where the protein-mediated caliper measurement of VLCFA length serves as the primary sensor for TORC2 nutrient-responsiveness, while subsequent lipid modifications govern the biophysical execution of cell size control.
    Keywords:  Cell growth; Cell size; Ceramides; TORC2; Yeast
    DOI:  https://doi.org/10.1242/bio.062633
  16. Cancer Res. 2026 May 05.
    Cancer-Associated Fibroblasts Promote Epithelial-Mesenchymal Transition and Classical to Basal Subtype Shift in Pancreatic Cancer.
    Kylie Belanger, Samantha Guinn, Brayan Perez, Yeonju Cho, Joseph A Tandurella, Mili Ramani, Jae W Lee, Daniel J Zabransky, Emma Kartalia, Jignasha Patel, Haley Zlomke, Norman G Nicolson, Nicole E Gross, Sarah M Shin, Benjamin C Barrett, Samantha Sun, Nicholas Sun, Ethan Firth, Alexei G Hernandez, Erin M Coyne, Courtney D Cannon, Eunji Moon, Soren Charmsaz, Ludmila Danilova, James M Leatherman, Melissa R Lyman, Jacob T Mitchell, Lei Zheng, Michael G Goggins, Kelly J Lafaro, Jin He, Christopher R Shubert, William R Burns, Elana J Fertig, Luciane T Kagohara, Elizabeth M Jaffee, Richard A Burkhart, Won Jin Ho, Jacquelyn W Zimmerman.
      Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer-associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy, and multiple CAF subtypes have been defined. However, defining the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior is required to better characterize the role of CAFs in PDAC. Here, we used multi-omic analyses to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs promoted epithelial-mesenchymal transition (EMT) and a switch in tumor cell classification from classical to basal subtype. Furthermore, CAF-specific interleukin 8 (IL-8) functioned as a modulator of tumor cell subtype. Finally, neighborhood relationships between tumor cells and T cell subsets were defined, demonstrating a distinct spatial coordination among CAF and tumor cell subtypes. Overall, this study provides data supporting CAF signaling as a regulator of the cellular and behavioral heterogeneity in the PDAC TME. These findings can be used to explore rational approaches to improve therapies for this difficult-to-treat disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0331
  17. Cancer Cell. 2026 May 07. pii: S1535-6108(26)00218-7. [Epub ahead of print]
    Whole-genome doubling drives immune evasion by silencing antigen presentation.
    Pierre Foidart, Zheqi Li, Xinran Cai, Marco Seehawer, Daniel D Brown, Amatullah Tawawalla, Pilar Baldominos, Salma Parvin, Jun Nishida, Ernesto Rojas-Jimenez, Triet M Bui, Benedetto Diciaccio, Rahul Kumar, Brent T Schlegel, Marie-Anne Goyette, TashJae Scales, Pengze Yan, Xintao Qiu, Rong Li, Yijia Jiang, Yingtian Xie, Mahmoud Aarabi, Xiao-Yun Huang, Laura E Stevens, Paloma Cejas, Lise Mangiante, Cristina Irene Sotomayor Vivas, Kathleen E Houlahan, Christina Curtis, Steffi Oesterreich, Isaac S Harris, Anthony G Letai, Adrian V Lee, Henry W Long, Judith Agudo, Kornelia Polyak.
      Whole-genome doubling (WGD) is a common yet poorly understood event associated with poor clinical outcomes. Here, we characterize mechanisms by which WGD drives tumor evolution, utilizing mouse mammary tumor models of WGD established through cell fusion. We find that WGD increases transcriptomic and epigenetic heterogeneity and identify the YM155 BIRC5 inhibitor as a compound specifically suppressing WGD+ tumors. WGD triggers immune evasion by escaping CD8+ T cell responses, rendering WGD+ tumors more sensitive to anti-PD-L1. Through single-cell profiling, we discover that WGD+ cancer cells exhibit reduced antigen presentation and response to IFNγ, attributed to the epigenetic silencing of MHCI transcriptional regulators via elevated histone H3 lysine 27 trimethylation. Further investigations reveal decreased KDM6 activity and increased succinate levels in WGD+ tumors. PRC2 inhibition preferentially suppresses WGD+ tumor growth, enhances antigen presentation, and CD8+ T cell infiltration. Our results underscore metabolic and epigenetic alterations as critical drivers of WGD-associated immune escape.
    Keywords:  antigen presentation; breast cancer; epigenetic silencing; immune escape; whole genome doubling
    DOI:  https://doi.org/10.1016/j.ccell.2026.04.007
  18. Acta Neuropathol. 2026 May 03. pii: 52. [Epub ahead of print]151(1):
    Lipofuscin accumulation in aging and CLN1 is associated with deficient de-S-acylation, lyso-mitochondrial dysfunction, and lipid dyshomeostasis.
    Sofia Massaro Tieze, Alexander Esqueda, Rachel McAllister, Matija Lagator, Betül Yücel, Eric Sun, Katherine B Henke, TuKiet T Lam, Nicholas Lockyer, Kallol Gupta, Sreeganga S Chandra.
      Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; CLN1) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses, and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of lipofuscin in the aged and CLN1 brain to be remarkably similar. Dissection of implicated molecular pathways reveals protein S-acylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and CLN1. Notably, > 95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that CLN1 lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration.
    Keywords:   CLN1 ; Aging; Autofluorescence; Lipid homeostasis; Lipofuscin; Lysosomal storage disorder; Mitochondria-lysosome axis; Neurodegeneration; Neuronal Ceroid Lipofuscinosis; Palmitoyl protein thioesterase 1; S-acylation
    DOI:  https://doi.org/10.1007/s00401-026-03012-7
  19. EMBO J. 2026 May 02.
    Peroxisome-derived ether lipids regulate lysosomal exocytosis.
    Liang Chen, Danielle Henn, Zhongzheng Dong, Jiaxuan Liang, Aleksander Wielenga, Goncalo Vale, Bala Burugula, Junyi Zou, Yamuna Krishnan, Jeffrey G McDonald, Jacob Kitzman, Ming Li.
      Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
    DOI:  https://doi.org/10.1038/s44318-026-00791-3
  20. Cancers (Basel). 2026 Apr 09. pii: 1205. [Epub ahead of print]18(8):
    Sarcopenia as a Marker of Immunometabolic Vulnerability in Pancreatic Ductal Adenocarcinoma.
    Mukund Karthik, Sara Shahrestani, Jin-Soo Park, Christian Ratnayake, Charbel Sandroussi.
      Despite advances in surgical technique and perioperative care, pancreatic ductal adenocarcinoma (PDAC) remains associated with poor survival. Sarcopenia is highly prevalent in PDAC and is consistently associated with inferior survival and reduced tolerance of systemic therapy. However, interventions primarily aimed at increasing muscle mass through nutritional supplementation and resistance-based exercise have yielded limited improvements in clinically meaningful postoperative outcomes. This has prompted increasing interest in sarcopenia as a marker of broader biological vulnerability rather than isolated physical deconditioning. Emerging clinical, translational, and experimental evidence demonstrates that skeletal muscle and adipose tissue function as active immunometabolic organs, and that cancer-associated inflammatory pathways drive early muscle loss, immune dysfunction, and impaired physiological recovery. Across multiple clinical cohorts, sarcopenia is reproducibly associated with worse overall survival and failure to complete adjuvant therapy, but not consistently with increased postoperative complications, suggesting that its prognostic relevance lies in impaired recovery and oncological fitness rather than immediate surgical risk. Translational studies further indicate that sarcopenia identifies patients with reduced antitumor immune competence, particularly in early-stage disease. This review synthesizes current evidence linking sarcopenia, immune dysfunction, and surgical outcomes in PDAC and examines implications for perioperative care. We propose that immunometabolic-informed prehabilitation, integrated with existing nutritional and exercise strategies, may represent a more effective approach to improving recovery, treatment tolerance, and durable oncological outcomes following PDAC resection.
    Keywords:  cancer cachexia; immune dysfunction; pancreatic cancer; prehabilitation; sarcopenia; surgery
    DOI:  https://doi.org/10.3390/cancers18081205
  21. bioRxiv. 2026 Apr 21. pii: 2026.04.16.719008. [Epub ahead of print]
    Acquired resistance to the PRMT5 inhibitor confers collateral sensitivity to MEK inhibition in MTAP-null non-small cell lung cancer.
    Rongjie Fu, Yalong Wang, Ishita Rehman, Ella Bedford, Sana Sharif, Nghi D Nguyen, Reid T Powell, Andrew Adams, Weijun Liu, Shuyue Wang, Wei He, Yue Lu, Bin Liu, Pooja Anil Shah, Jordi Rodon Ahnert, Taiping Chen, Weiyi Peng, Clifford C Stephan, Xinli Liu, Mark T Bedford, Han Xu.
      Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation MTA-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated mechanisms of acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro -derived resistant models, we found that acquired resistance was not fully explained by alterations in PRMT5 activity or reduced MTA levels. Instead, resistance was associated with collateral sensitivity to MEK inhibition and enrichment of MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as an actionable collateral vulnerability in MTAP-null NSCLC cells that acquire resistance to PRMT5 inhibition.
    DOI:  https://doi.org/10.64898/2026.04.16.719008
  22. bioRxiv. 2026 Apr 27. pii: 2026.04.24.720406. [Epub ahead of print]
    Selective Editing and Functionalization of the Mammalian Lipidome.
    Binyou Wang, Lukas Lüthy, Logan Tenney, Leo Qi, Takeshi Harayama, Kim Ekroos, Johannes Morstein.
      Lipids exhibit extraordinary molecular diversity, yet tools to selectively manipulate defined lipid classes in living cells are lacking. Here we show that lipid tail structure biases metabolic fate, enabling the design of synthetic lipid analogs with programmable metabolic selectivity. This approach enables selective cellular production of distinct lipid species or subclasses, including types of neutral lipids, phospholipids, sphingolipids, and ether lipids, without genetic or enzymatic perturbation. We further couple metabolic selectivity to chemical functionalization using bifunctional lipids, in which one modification directs metabolic flux and a second enables bioorthogonal tagging. Using this strategy, we achieve selective in situ labeling of different lipid pools in living cells. Together, our work establishes a chemical biology strategy that enables unprecedented precision in modulating, functionalizing, and rewiring the mammalian lipidome.
    DOI:  https://doi.org/10.64898/2026.04.24.720406
  23. Nat Rev Dis Primers. 2026 May 07. pii: 23. [Epub ahead of print]12(1):
    Pancreatic cancer.
    Susanne Roth, Minoti Apte, Vinod P Balachandran, Giulia Biffi, Thierry Conroy, Edna Cukierman, Efrat Dotan, Irene Esposito, Barbara T Grünwald, Miriam Klauß, Alison P Klein, Núria Malats, Eileen M O Reilly, Mike J Pishvaian, Francisco X Real, Dieter Saur, Jens T Siveke, Christoph W Michalski.
      Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, characterized by late diagnosis, aggressive biology and limited therapeutic success. Advances in multiagent chemotherapy have improved outcomes across disease stages, whereas precision medicine approaches are reshaping treatment paradigms. Personalized RNA vaccines and oncogenic KRAS-directed agents represent emerging immunological and molecular frontiers. Multimodal treatment regimens and surgical innovations, including vessel-oriented and minimally invasive techniques, have enhanced complete resection rates and enabled conversion of initially unresectable locally advanced pancreatic cancer into resectable disease. Increasingly, multidisciplinary, biology-guided strategies define resectability and the sequence of systemic and local therapies. The tumour microenvironment's complex stromal and immune ecology remains central to therapeutic resistance but also offers opportunities for rational combination therapy. Early detection and risk-adapted surveillance for high-risk individuals are advancing, as are artificial intelligence-assisted imaging and liquid biopsy approaches. Despite persistent challenges, the convergence of mechanistic insights, precision therapeutics and supportive care provides a framework for transforming pancreatic ductal adenocarcinoma from an inevitably lethal disease towards a better manageable condition.
    DOI:  https://doi.org/10.1038/s41572-026-00699-6
  24. ArXiv. 2026 May 04. pii: arXiv:2504.04305v3. [Epub ahead of print]
    FILM: Mapping organellar metabolism by mid-infrared photothermal modulated fluorescence.
    Jianpeng Ao, Jiaze Yin, Haonan Lin, Guangrui Ding, Youchen Guan, Bethany Weinberg, Dashan Dong, Qing Xia, Zhongyue Guo, Marzia Savini, Biwen Gao, Ji-Xin Cheng, Meng C Wang.
      Metabolism unfolds within specific organelles in eukaryotic cells. Lysosomes are highly metabolically active organelles, and their metabolic states dynamically influence signal transduction, cellular homeostasis, and organismal physiopathology. Despite the significance of lysosomal metabolism, a method for its in vivo measurement is currently lacking. Here, we report optical boxcar-enhanced, fluorescence-detected mid-infrared photothermal microscopy, together with AI-assisted data denoising and spectral deconvolution, to map metabolic activity and composition of individual lysosomes in living cells and organisms. Using this method, we uncovered lipolysis and proteolysis heterogeneity across lysosomes within the same cell, as well as early-onset lysosomal dysfunction during organismal aging. Additionally, we discovered organelle-level metabolic changes associated with diverse lysosomal storage diseases. This method holds the broad potential to profile metabolic fingerprints of individual organelles within their native context and quantitatively assess their dynamic changes under different physiological and pathological conditions, providing a high-resolution chemical cellular atlas.
  25. Theranostics. 2026 ;16(11): 6315-6349
    Unraveling autophagy-metabolism crosstalk in cancer: Molecular insights and therapeutic strategies.
    Haoyou Wang, Qianqian Yang, Yingying Lu, Cheng Du, Wei Wang, Lan Zhang.
      Autophagy is a catabolic process essential for the degradation and recycling of damaged proteins and organelles, thereby contributing to the maintenance of cellular homeostasis and the integrity of the intracellular environment. Although autophagy serves protective physiological functions, its involvement in various diseases, particularly cancer, is complex and context-dependent. In the context of tumor development, autophagy plays two distinct roles. During the early stages of tumorigenesis, it functions as a tumor suppressor by preserving genomic stability. In later stages, however, it promotes tumor growth, supports the survival of cancer cells, and contributes to therapeutic resistance. Cancer cells are known to change their metabolic processes to support growth and division. Autophagy and metabolism work together, enabling cells to utilize both external and internal resources to generate energy and synthesize new molecules. This interaction is especially important in the stressful environment of tumors, like when there's not enough food or oxygen. In these situations, autophagy helps the tumor adapt metabolically and grow by breaking down and reusing parts inside the cell. In this review, we systematically examine the role of autophagy as a key regulator that coordinates diverse metabolic programs in cancer cells. We focus on central metabolic pathways, including glycolysis, lipid metabolism, and amino acid metabolism, as well as emerging regulatory networks involving nucleotide metabolism and mitochondrial metabolism. Importantly, we highlight how these metabolic pathways are dynamically integrated through autophagy to facilitate tumor adaptation, support metabolic plasticity, and drive therapeutic resistance.
    Keywords:  autophagy; cancer; metabolic reprogramming; metabolism; small-molecule drugs
    DOI:  https://doi.org/10.7150/thno.132362
  26. Cell Death Discov. 2026 May 07.
    RHOV couples EMT-associated plasticity to cytoskeletal execution of invasion and metastasis.
    Qi Wang, Yaru Zhao, Shenghui Huang, Haiyan Fu, Chiara Reina, Alexandra Aicher, Jiajia Tang, Christopher Heeschen.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by early invasion and rapid metastatic dissemination, yet the cytoskeletal mechanisms that enable these aggressive behaviors remain incompletely defined. Here, we identify the atypical Rho GTPase RHOV as a critical regulator of invasive progression and metastasis in PDAC. Integrated analyses of independent patient cohorts, patient-derived models, and single-cell transcriptomic datasets revealed that RHOV is selectively overexpressed in malignant epithelial cells, with high RHOV expression correlating with advanced disease stage and poor patient survival. Genetic suppression or deletion of RHOV impaired PDAC cell invasion, migration, clonogenic growth, and context-dependent sphere formation in vitro, while reducing tumor-initiating capacity and metastatic colonization in vivo. Mechanistically, RHOV maintains BRK1-dependent WAVE regulatory complex integrity to sustain lamellipodia formation and invasive motility. Loss of RHOV uncoupled EMT-associated transcriptional programs from cytoskeletal execution of invasion, resulting in compensatory EMT gene expression without restoration of invasive behavior. Re-expression of BRK1 rescued invasion defects following RHOV inhibition. Together, these findings identify RHOV as an executional dependency that enables PDAC invasiveness by linking transcriptional plasticity to actin-based motility.
    DOI:  https://doi.org/10.1038/s41420-026-03137-4
  27. J R Soc Interface. 2026 May 06. pii: 20250754. [Epub ahead of print]23(238):
    Do crowded phospholipid monolayers remain fluid?
    Damian Renggli, Maria Clara Novaes-Silva, Demetrios Laios, Laura Stricker, Jan Vermant.
      Phase separation in mixed lipid layers is used here to mimic crowding at interfaces, providing insights into the dynamics of (and within) phospholipid monolayers. The interface is fully fluid at temperatures above the liquid-condensed (LC) phase melting point for the range of accessible interfacial pressures. Upon cooling, temperature-induced phase separation occurs. We moreover control the solid-like LC phase fraction by tuning the lipid composition between dipalmitoyl-phosphatidylcholine (DPPC) and dioleoyl-phosphatidylcholine (DOPC). Interfacial rheology reveals a strong viscoelastic response in DPPC monolayers at physiologically relevant pressures and sub-30∘C temperatures. Mixed monolayers exhibit viscosity scaling with increasing LC phase fraction, behaving somewhat as a suspension of discs. However, we observe weak aggregation and deviations from hard-disc models. This suggests that phase coexistence preserves the effective interface fluidity by mitigating hydrodynamic jamming; this could possibly also be a mechanism governing membrane dynamics in crowded states.
    Keywords:  interfacial rheology; phospholipid bilayers; phospholipid monolayers
    DOI:  https://doi.org/10.1098/rsif.2025.0754
  28. Sci Adv. 2026 May 08. 12(19): eaeb6691
    Reconstituted nascent adhesion condensates drive actin polymerization on supported lipid bilayers.
    Arsenii Hordeichyk, Kristian A T Pajanonot, Chiao-Peng Hsu, Timon Nast-Kolb, Lukas J Neumann, Reinhard Fässler, Andreas R Bausch.
      Nascent adhesions are early integrin-based assemblies that couple the extracellular matrix to the actin cytoskeleton and mature into focal adhesions. Many nascent-adhesion proteins interact through weak, multivalent contacts, suggesting that liquid-like organization may contribute to adhesion assembly. However, how phase separation shapes actin polymerization and organization remains unclear. Here, we compare two vasodilator-stimulated phosphoprotein (VASP)-recruiting adaptor proteins, zyxin and vinculin, to determine how adaptor identity tunes condensate properties and actin coupling. Both zyxin-VASP and vinculin-VASP assemblies drive integrin clustering and support actin filament growth. Notably, zyxin-VASP condensates remain fluid and redistribute along newly formed actin bundles, whereas vinculin-VASP condensates are more rigid and fail to spread along actin despite sustaining polymerization. These results suggest that differential VASP recruitment can modulate condensate properties and actin architecture, providing a potential mechanism for the maturation of nascent adhesions into focal adhesions.
    DOI:  https://doi.org/10.1126/sciadv.aeb6691
  29. Trends Cancer. 2026 May 07. pii: S2405-8033(26)00078-6. [Epub ahead of print]
    Bioengineered systems to exploit tumor microenvironment metabolism.
    Christine Sanganoo, Ilaria Caturegli, Zachary Mattes, Jordan Ryan, Wilson W Wong, Mark W Grinstaff.
      Our understanding of cancer metabolism has afforded the opportunity to develop therapies specific to tumor metabolic dysregulation. While molecular therapeutics targeting cancer metabolism have found success in the clinic, bioengineering approaches are nascent. Here, we describe key metabolic pathways and their genetic dysregulations in the tumor microenvironment (TME) that are ripe for intervention. We examine bioengineered biomaterial and cellular systems that harness the metabolic and immune landscape of the TME to target metabolic dependencies of tumor growth. These therapeutic strategies include, for example, preventing the uptake of essential metabolites, delivering metabolic inhibitors, and restoring an immunostimulating environment. With a focus toward clinical applications and tolerability, we identify key limitations and conclude with future directions.
    Keywords:  antimetabolite delivery; biomaterials; cancer metabolism; immunosuppressive metabolite modulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.04.003
  30. Ann Surg. 2026 May 04.
    Implantable Microdevices for In Vivo Assessment of Chemotherapy Response in Patient Derived Organoid Orthotopic Pancreatic Cancer Models.
    Oliver J Standring, Julien T Hohenleitner, Lyudmyla Demyan, Shruti Koti, Nandan Vithlani, Taemoon Chung, Amber N Habowski, Taehoon Ha, Sepideh Gholami, James M Crawford, Youngkyu Park, Oliver Jonas, Zhen Zhao, Scott K Lyons, Daniel A King, David A Tuveson, Matthew J Weiss.
       OBJECTIVE: To investigate the feasibility of using implantable microdevices (IMDs) in pancreatic ductal adenocarcinoma (PDAC).
    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited treatment options. IMDs permit localized delivery of multiple therapies with simultaneous in vivo assessment of tumor response. Although IMDs have previously been evaluated in multiple malignancies, their application in PDAC has not been reported.
    METHODS: Xenograft tumors were generated by injecting PDAC patient-derived organoids (PDO) into mouse pancreata. IMDs loaded with standard-of-care chemotherapeutic drugs including gemcitabine, paclitaxel, SN38 (irinotecan metabolite), oxaliplatin, and 5-fluorouracil were then inserted into the tumor during laparotomy. Mice were sacrificed at 4 or 24 hours after insertion. Immunofluorescence was performed to assess biomarkers of DNA damage (γH2AX), apoptosis (cleaved caspase-3; CC3), and proliferation (Ki67).
    RESULTS: Fourteen mice underwent IMD placement with successful device retrieval and analysis. CC3 and γH2AX analyses revealed treatment specific biologic response, with the most pronounced response at 24 hours. Ki67 analysis demonstrated reduction of the proliferation within treated regions at both 4 and 24 hours compared to controls. Overall, the IMD enabled localized chemotherapy delivery and concurrent assessment of responses to multiple chemotherapeutic agents in an in vivo setting.
    CONCLUSION: Intra-pancreatic IMD deployment in orthotopic PDAC organoid tumors presents a feasible approach to assess chemotherapy sensitivities. Changes in proliferation revealed drug specific response at all timepoints, while apoptotic markers required longer incubation. These data support further investigation into the intra-operative or endoscopic deployment of IMDs as a platform for precision medicine.
    Keywords:  Cleaved Caspase 3, yH2AX; Implantable Microdevice; Ki67; Patient Derived Organoid; biomarkers; chemotherapy; pancreatic cancer
    DOI:  https://doi.org/10.1097/SLA.0000000000007071
  31. Autophagy. 2026 May 06. 1-3
    When tau stalls the lysosome: decoupling trafficking and degradation in autophagy.
    Celeste M Karch, Farzaneh S Mirfakhar.
      Tauopathies are characterized by the accumulation of misfolded tau and lysosomal dysfunction, yet whether defects in the autophagy-lysosome pathway are causal or secondary remains unclear. Recent work using human iPSC-derived neurons harboring the MAPT p.R406W mutation demonstrates that pathogenic tau is sufficient to disrupt lysosomal function upstream of tau accumulation. Tau species are differentially processed within lysosomes, with phosphorylated tau retained at the lysosomal membrane, consistent with a barrier to efficient cargo processing. Importantly, pharmacologic activation of autophagy restores degradative capacity and reduces tau burden without rescuing lysosomal motility, suggesting that trafficking and degradation represent separable axes of lysosomal biology. These findings position tau as an active disruptor of proteostasis and define a degradative bottleneck that shares features with lysosomal storage disorders. Together, this work reframes autophagy dysfunction in tauopathy as a modular defect with distinct therapeutic entry points.
    Keywords:  Induced pluripotent stem cells; MAPT; lysosomal trafficking; neurons; tauopathy
    DOI:  https://doi.org/10.1080/15548627.2026.2669685
  32. Science. 2026 May 07. eaec8514
    TranscriptFormer: A generative cell atlas across 1.5 billion years of evolution.
    James D Pearce, Sara E Simmonds, Gita Mahmoudabadi, Lakshmi Krishnan, Giovanni Palla, Ana-Maria Istrate, Alexander Tarashansky, Benjamin Nelson, Omar Valenzuela, Donghui Li, Stephen R Quake, Theofanis Karaletsos.
      Single-cell transcriptomics is revolutionizing our understanding of cellular diversity, yet comparing transcriptional programs across the tree of life remains challenging. We developed TranscriptFormer, a family of generative foundation models trained on up to 112 million cells spanning 1.53 billion years of evolution across 12 species. We demonstrate state-of-the-art performance on cell type classification, even for species separated over 685 million years of evolution, and zero-shot disease state identification in human cells. Developmental trajectories, phylogenetic relationships and cellular hierarchies emerge naturally in TranscriptFormer's representations without any explicit training on these annotations. This work establishes a powerful framework for quantitative single-cell analysis and comparative cellular biology, thus demonstrating that universal principles of cellular organization can be learned and predicted across the tree of life.
    DOI:  https://doi.org/10.1126/science.aec8514
  33. medRxiv. 2026 Apr 22. pii: 2026.04.21.26351329. [Epub ahead of print]
    Novel Genetic Risk Loci for Pancreatic Ductal Adenocarcinoma Identified in a Genome-wide Study of African Ancestry Individuals.
    Candelaria Vergara, Zhanmo Ni, Jun Zhong, David McKean, Katelyn E Connelly, Samuel O Antwi, Alan A Arslan, Paige M Bracci, Mengmeng Du, Steven Gallinger, Jeanine Genkinger, Christopher A Haiman, Manal Hassan, Rayjean J Hung, Chad Huff, Charles Kooperberg, Fay Kastrinos, Loic LeMarchand, WooHyung Lee, Shannon M Lynch, Stephen C Moore, Ann L Oberg, Margaret A Park, Jennifer B Permuth, Harvey A Risch, Paul Scheet, Ann Schwartz, Xiao-Ou Shu, Rachael Z Stolzenberg-Solomon, Brian M Wolpin, Wei Zheng, Demetrius Albanes, Gabriella Andreotti, William R Bamlet, Laura Beane-Freeman, Sonja I Berndt, Paul Brennan, Julie E Buring, Natalia Cabrera-Castro, Daniele Campa, Federico Canzian, Stephen J Chanock, Yu Chen, Charles C Chung, A Heather Eliassen, J Michael Gaziano, Graham G Giles, Edward L Giovannucci, Michael Goggins, Phyllis J Goodman, Belynda Hicks, Amy Hutchinson, Miranda R Jones, Verena Katzke, Manolis Kogevinas, Robert C Kurtz, Daniel Laheru, I-Min Lee, Núria Malats, Roger Milne, Lorelei Mucci, Rachel E Neale, Irene Orlow, Alpa V Patel, Laia Peruchet, Ulrike Peters, Miquel Porta, Kari G Rabe, Francisco X Real, Fulvio Ricceri, Nathaniel Rothman, Howard D Sesso, Veronica W Setiawan, Debra Silverman, Melissa C Southey, Meir J Stampfer, Geoffrey S Tobias, Caroline Um, Kala Visvanathan, Jean Wactawski-Wende, Nicolas Wentzensen, Walter C Willett, Herbert Yu, Peter Kraft, Priya Duggal, Laufey T Amundadottir, Alison P Klein.
      Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors.
    Statement of Significance: To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.
    DOI:  https://doi.org/10.64898/2026.04.21.26351329
  34. J Cell Biol. 2026 Jun 01. pii: e202504130. [Epub ahead of print]225(6):
    Phosphatidylserine is a component of the gradient-tracking machine in mating yeast.
    Chih-Yu Pai, Xin Wang, Hamida Mahmood, David E Stone.
      Chemotropism, the ability to orient growth toward external chemical cues, is a fundamental process in diverse eukaryotic systems. During mating, budding yeast cells detect pheromone gradients from potential partners, locating them by assembling a gradient-tracking machine (GTM) at the plasma membrane that redistributes upgradient prior to polarized growth. Although membrane lipids are known to influence pheromone signaling and morphogenesis, their roles in pre-morphogenic gradient tracking have remained unclear. Here, we show that phosphatidylserine (PS), phosphatidylinositol-4,5-bisphosphate, and ergosterol exhibit GTM-like dynamics, polarizing to the default polarity site, redistributing upgradient, and stabilizing at the chemotropic site. Blocking PS synthesis causes a severe and specific gradient-tracking defect, whereas disruption of Bem1 binding to anionic lipids slows but does not abolish tracking. Analysis of polarity, Cdc42 activity, and exocyst dynamics indicates that Bem1 membrane binding contributes to spatial focusing of Cdc42 activation during tracking but cannot account for the pronounced defects caused by PS loss, indicating that PS influences gradient tracking through multiple GTM components. In contrast, ergosterol is dispensable for tracking but required for proper receptor organization and partner alignment after GTM stabilization. Together, these findings establish membrane lipids as integral GTM components and highlight PS as a key regulator of chemotropic gradient sensing through multivalent protein-lipid interactions.
    DOI:  https://doi.org/10.1083/jcb.202504130
  35. Elife. 2026 May 07. pii: e111373. [Epub ahead of print]15
    How membranes shape up for lipid transfer.
    Takashi Hirashima, Toshiya Endo.
      The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.
    Keywords:  biochemistry; cardiolipin; chemical biology; lipid transport; mitochondria; none; phosphatidic acid
    DOI:  https://doi.org/10.7554/eLife.111373
  36. Elife. 2026 May 05. pii: RP106587. [Epub ahead of print]14
    Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
    David Papadopoli, Ranveer Palia, Predrag Jovanovic, Sébastien Tabariès, Emma Ciccolini, Valerie Sabourin, Sebastian Igelmann, Shannon McLaughlan, Lesley Zhan, HaEun Kim, Nabila Chekkal, Krzysztof J Szkop, Thierry Bertomeu, Jibin Zeng, Julia Vassalakis, Farzaneh Afzali, Slim Mzoughi, Ernesto Guccione, Mike Tyers, Daina Avizonis, Ola Larsson, Lynne-Marie Postovit, Sergej Djuranovic, Josie Ursini-Siegel, Peter M Siegel, Michael Pollak, Ivan Topisirovic.
      Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.
    Keywords:  cancer biology; cell biology; human; mRNA translation; metabolism; mouse; signal transduction
    DOI:  https://doi.org/10.7554/eLife.106587
  37. Nat Cancer. 2026 May 07.
    A high-MAPK, low-WNT cell state drives metastatic dissemination in colorectal cancer.
    Melanie Heinlein, Ginny X Li, Noelyn Kljavin, Amanda R Moore, Brian Biehs, Liming Tao, Soufiane Boumahdi, Farnaz Mohammadi, Minyi Shi, Yuxin Liang, Hartmut Koeppen, Nicolò Riggi, Robert Piskol, Frederic J de Sauvage.
      Colorectal cancer (CRC), a leading cause of cancer-related mortality due to distant metastases, is largely driven by activating mutations in the WNT and mitogen-activated protein kinase (MAPK) pathways. Understanding the mechanism underlying the metastatic process is essential for developing effective treatments. Using serial in vivo orthotopic passaging, we developed an immunocompetent mouse model of metastatic CRC. Highly metastatic tumor cells exhibited chromosomal amplifications in MAPK pathway genes, resulting in increased MAPK pathway activity and suppression of WNT-associated transcriptional programs, including stem cell genes. Pharmacological inhibition of mutant KRASG12D led to a reduction in the MAPK-high-WNT-low transcriptional state and decreased both lung and liver metastases. Analysis of CRC patient data revealed that the metastatic gene signature associated with the MAPK-high-WNT-low state correlated with poorer survival outcomes. These findings underscore the plasticity of metastasis-initiating cells in CRC driven by the opposing roles of MAPK and WNT signaling, despite their synergy observed during colon tumorigenesis.
    DOI:  https://doi.org/10.1038/s43018-026-01155-w
  38. Redox Biol. 2026 Apr 30. pii: S2213-2317(26)00193-X. [Epub ahead of print]94 104195
    Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.
    Lianne Jhc Jacobs, Sebastian Doll, Dietrich Trümbach, Matteo Veronese, Giada Di Pietro, Fatma Isil Yapici, Lidwina Hasberg, Pascal Gentzsch, Sarah Gerlich, Jens Hansen, Silvia von Karstedt, Elena I Rugarli, Marcus Conrad, Armindo Salvador, Jan Riemer.
      Hydrogen peroxide (H2O2) plays a dual role as both a signalling molecule and a mediator of oxidative stress. Although mitochondria are major producers of H2O2, the relative contributions of mitochondrial versus cytosolic antioxidant systems to mitochondrial H2O2 homeostasis in intact cells remain poorly defined. Here, we combined compartment-resolved live-cell imaging using HyPer7, inducible mitochondrial H2O2 generation (matrix-targeted d-amino acid oxidase), kinetic modelling, and a targeted CRISPR/Cas9 screen to dissect determinants of mitochondrial H2O2 dynamics in HEK293 cells. Unexpectedly, we found that the cytosolic peroxiredoxin PRDX1 is a dominant regulator of mitochondrial matrix H2O2 levels. Loss of cytosolic PRDXs markedly enhanced matrix Hyper7 signals under both exogenous and mitochondria-intrinsic H2O2 production, exceeding the effects of deleting mitochondrial peroxiredoxins. Modelling and transport experiments indicated a very high permeability of the mitochondrial inner membrane to H2O2 enabling rapid efflux and the establishment of steep concentration gradients. This permits the cytosol to function as a major sink to limit matrix H2O2 accumulation. PRDX1 deficiency sensitized cells to chronic mitochondrial oxidative stress. A targeted CRISPR screen identified the Rab7 GAP TBC1D5, linking mitophagy to cellular survival under these conditions. Consistently, PRDX1/2-deficient cells exhibited elevated mitophagic flux, indicating mitochondrial quality control as a compensatory response. Our study reveals that cytosolic PRDXs critically impact mitochondrial redox homeostasis and provides a systems-level framework for understanding compartmental redox control and stress adaptation.
    DOI:  https://doi.org/10.1016/j.redox.2026.104195
  39. Nat Commun. 2026 May 05.
    NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer.
    Pavla Ticha, Jason J Northey, Radhika Narain, Shivang Sharma, Johnathon N Lakins, Hugo Gonzalez, Kelly Kersten, Alastair J Ironside, Allison P Drain, Martin Zidek, Kelvin K Tsai, Yunn-Yi Chen, Eugene Shenderov, Valerie M Weaver.
      Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. Major Histocompatibility Complex (MHC)-mediated antigen presentation facilitates T cell-dependent eradication of metastatic tumor cells. Here, we show that nuclear corepressor 2 (NCOR2) is an epigenetic regulator of MHC class I molecule presentation on breast tumor cells. Patients with triple negative breast cancer (TNBC) that express high levels of NCOR2 also exhibit reduced metastasis-free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC have high nuclear NCOR2 and reduced Cluster of Differentiation (CD)8+ T cells. Reducing NCOR2 expression or preventing its interaction with Histone Deacetylase, HDAC3, enhances innate immune cell recruitment and activity, and elevates MHC class I levels on disseminated cancer cells to potentiate CD8+ T cell activity and apoptosis induction that prevents metastatic progression. The studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.
    DOI:  https://doi.org/10.1038/s41467-026-72168-3
  40. RSC Chem Biol. 2026 Apr 23.
    Decoding protein-phospholipid interaction networks in cancer: the role of acyl-chain remodeling.
    Berit Blume, Grace Potter, Carsten Schultz, Andrew Emili.
      Lipids, particularly phosphoinositides, are increasingly recognized as important markers and causal regulators in cancer progression. Less appreciated, however, are the functional consequences of changes in phospholipid acyl chain length and saturation. These alterations reshape membrane biophysics and rewire membrane-associated signaling complexes, suggesting that acyl-chain remodeling represents an emerging regulatory layer in cancer biology. Distinct tumor types or their models exhibit characteristic acyl chain profiles, often shifting toward shorter, more saturated chains that alter physical and functional interactions. Stress conditions and the tumor microenvironment further diversify these profiles, linking acyl chain composition to cellular plasticity, invasiveness, and metastatic potential. In this review, we summarize the molecular factors and enzymatic pathways that govern phospholipid acyl chain remodeling in cancer and examine their relevance to dynamic protein interaction networks. We describe how dysregulated lipid metabolism at the fatty acid level intersects with oncogenic signaling and highlight emerging chemical biology and multi-omics approaches that enable interrogation of protein-phospholipid interaction networks in physiological contexts. Together, these developments position acyl chain-resolved lipid analysis as a central challenge in chemical biology, requiring new probe design and integrative data frameworks to decode lipid-protein interaction networks in cancer. Finally, we discuss how emerging tools for acyl chain-resolved lipid analysis and targeted modulation reveal how membrane remodeling rewires signaling pathways and reshapes the tumor lipid-protein interactome, opening new opportunities for cancer diagnosis and therapeutic intervention.
    DOI:  https://doi.org/10.1039/d6cb00015k
  41. bioRxiv. 2026 Apr 21. pii: 2026.04.18.719315. [Epub ahead of print]
    Foundation cell segmentation models performance on live microscopy and spatial-omics data.
    Yang Miao, Nick Surguladze, Josh Lerner, Koravit Poysungnoen, Ky Ariano, Yuexi Li, Yining Zhu, Kyra Van Batavia, Jodie Jepson, Josie Van De Klashorst, Bobby Y X Ni, Alexander Armstrong, Reeha Rahman, Roarke Horstmeyer, John W Hickey.
      Accurate cell segmentation is an essential step for quantitative analysis of biological imaging data. Recent advances in deep learning have led to the development of generalist segmentation models that perform robustly across multiple imaging modalities, including label-free phase contrast, fluorescence cell culture, and multiplexed fluorescence tissue imaging. However, systematic comparisons of these models at the level of downstream biological analysis remain limited. To address this gap, we evaluated several recent segmentation models, including Cellpose cyto3, Cellpose-SAM, μSAM, and CellSAM, on phase contrast and fluorescence cell culture images. In addition, Mesmer and InstanSeg were included for benchmarking on multiplexed fluorescence tissue images generated using CO-Detection by IndEXing (CODEX). We found that Cellpose-SAM achieved strong performance on phase contrast images, while SAM-based models consistently performed well on fluorescence cell culture data. In contrast, no single model consistently outperformed others on CODEX datasets. Instead, each model exhibited distinct strengths and limitations, which led to differences in downstream analyses, including clustering and cell type identification. Together, our study emphasizes the importance of selecting segmentation models based on dataset characteristics and analytical goals, rather than relying on a single universal approach.
    DOI:  https://doi.org/10.64898/2026.04.18.719315
  42. PLoS Genet. 2026 May 07. 22(5): e1012150
    Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations.
    Chang Liu, Sofya Golenkina, Natasha Fahey, Priya Kumar, Louise Y Cheng.
      Cancer cachexia is a multifactorial syndrome characterized by systemic metabolic dysfunction, including liver steatosis. In this study, we examined the role of larval oenocytes - hepatocyte-like cells, in a Drosophila model of cancer cachexia. We found that oenocytes in tumour-bearing larvae accumulate lipid droplets in response to tumour-secreted signals, Gbb and ImpL2. This lipid accumulation reflects systemic changes in lipid metabolism, responding to lipid metabolism manipulations in either the fat body or the muscle. Disrupting lipid synthesis/breakdown (via FASN1 and Bmm), storage (via Lsd2), or trafficking (via apolipoproteins) in these tissues significantly modulated lipid droplet accumulation in oenocytes. Moreover, oenocyte-specific knockdown of FASN1 reduced their lipid content and non-autonomously affected lipid droplet size in the fat body, suggesting cross-regulatory interactions between these tissues. Cachectic oenocytes also exhibited altered signaling profiles, characterized by reduced PI3K signalling. Enhancing PI3K signalling through Akt overexpression restored oenocyte size and reduced lipid levels; however, these changes did not significantly improve muscle integrity. Together, our data suggests that dynamic exchange of lipids occur between the fat body, oenocytes and the muscle during cancer cachexia. While the fat body and muscle lipid pools are key regulators of muscle integrity, oenocytes - despite their metabolic responsiveness, do not appear to play an active role in preserving muscle function during cachexia.
    DOI:  https://doi.org/10.1371/journal.pgen.1012150
  43. Nature. 2026 May 06.
    25 years of chemistry that simply clicks.
    Willow A Davis, Ellen M Sletten.
      
    Keywords:  Chemical biology; Drug discovery; Materials science; Organic chemistry
    DOI:  https://doi.org/10.1038/d41586-026-01155-x
  44. Redox Biochem Chem. 2025 Jun;pii: 100054. [Epub ahead of print]12
    Chemical Mechanisms of Lipid Peroxidation.
    Ned A Porter.
      The chemical framework for free radical chain oxidation of naturally-occurring lipids, commonly referred to as peroxidation, has provided a basis for understanding important processes in biology. H-atom transfer to peroxyl free radicals and olefin addition of those radicals are the primary rate-determining steps in peroxidation, but the lipid carbon radicals generated in these primary steps have multiple mechanistic pathways available. Oxygen addition, homolytic intramolecular substitution (s H i) and various cyclization reactions of intermediate peroxyl and alkoxyl radicals leads to a diverse set of products from polyunsaturated fatty acids and phospholipid esters. 5,7-Diene sterols are particularly reactive H-atom donors and give rise to complex product mixtures. The mechanistic guidelines for the important transformations of lipid peroxidation are summarized here and the connection between these fundamental chemical conversions and important enzymatic and non-enzymatic biological processes are outlined.
    DOI:  https://doi.org/10.1016/j.rbc.2025.100054
  45. Nat Methods. 2026 May 07.
    FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
    Jianpeng Ao, Jiaze Yin, Haonan Lin, Guangrui Ding, Youchen Guan, Marzia Savini, Bethany Weinberg, Dashan Dong, Qing Xia, Zhongyue Guo, Bowen Liu, Biwen Gao, Ji-Xin Cheng, Meng C Wang.
      Metabolism unfolds within specific organelles in eukaryotic cells. Lysosomes are highly metabolically active organelles, and their metabolic states dynamically influence signal transduction, cellular homeostasis and organismal physiopathology. Despite the importance of lysosomal metabolism, a method for its in vivo measurement is currently lacking. Here we report a fluorescence-detected mid-infrared photothermal microscope (FILM) implemented with optical boxcar demodulation, artificial intelligence-assisted data denoising and spectral deconvolution, to map metabolic activity and composition of individual lysosomes in living cells and organisms. Using this method, we uncovered lipolysis and proteolysis heterogeneity across lysosomes within the same cell, as well as early-onset lysosomal dysfunction during organismal aging. In addition, we discovered organelle-level metabolic changes associated with diverse lysosomal storage diseases. This method holds the broad potential to profile metabolic fingerprints of individual organelles within their native context and quantitatively assess their dynamic changes under different physiological and pathological conditions, providing a high-resolution chemical cellular atlas.
    DOI:  https://doi.org/10.1038/s41592-026-03090-1
  46. STAR Protoc. 2026 May 07. pii: S2666-1667(26)00196-6. [Epub ahead of print]7(2): 104543
    Protocol to determine in vitro lipid-protein interactions using liposome flotation assay.
    Karan Khadayat, Morgan House, Vasudeva Tati, Amit S Joshi.
      Lipid-protein interactions are crucial for cellular metabolism, transport, and signaling. Here, we present a detailed protocol to determine lipid-protein interactions using purified proteins, commercially available lipids, and a gradient centrifugation-based technique. We show how to make liposomes, test liposome size, form sucrose gradients with liposomes and purified protein, and collect and analyze the fractions after centrifugation. This protocol can determine lipid-protein interactions using a variety of liposome compositions for different proteins. For complete details on the use and execution of this protocol, please refer to House et al.1.
    Keywords:  Cell Membrane; Cell culture; Cell isolation; Cell separation/fractionation; Cell-based Assays; Flow Cytometry
    DOI:  https://doi.org/10.1016/j.xpro.2026.104543
  47. Molecules. 2026 Apr 16. pii: 1298. [Epub ahead of print]31(8):
    Oxidized Phosphatidylcholines Regulate Secretory Phospholipase A2 Through Membrane Nanodomain Remodeling.
    Vesela Yordanova, Rusina Hazarosova, Victoria Vitkova, Ralitsa Angelova, Biliana Nikolova, Atanaska Elenkova, Albena Momchilova, Galya Staneva.
      Oxidative stress generates oxidized phospholipids (OxPLs) that alter membrane structure and inflammatory lipid signaling, yet the underlying biophysical mechanisms remain poorly understood. Here, we examine how two structurally distinct truncated oxidized phosphatidylcholines (OxPCs), 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC), remodel membrane lateral organization and regulate secretory phospholipase A2 (sPLA2) activity. Large unilamellar vesicles composed of sphingomyelin, cholesterol, and either monounsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or polyunsaturated 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (PDPC) were used to reconstitute the liquid-ordered/liquid-disordered (Lo/Ld) phase coexistence characteristic of eukaryotic plasma membranes. Fluorescence spectroscopy revealed that OxPLs modulate lipid packing and nanodomain organization in a structure- and composition-dependent manner. POVPC promoted pronounced membrane ordering and Lo domain stabilization compared with PGPC, particularly in monounsaturated membranes with low cholesterol content. In contrast, PDPC-containing membranes, especially at elevated cholesterol, exhibited enhanced structural resilience to OxPL-induced perturbations. These biophysical changes were associated with distinct functional outcomes. Notably, the relationship between membrane structural parameters and sPLA2 activity was not linear, indicating a decoupling between bulk membrane properties and enzymatic response. sPLA2 activity was linked to membrane lateral organization: the size of Lo domains modulate hydrolysis by influencing the physicochemical properties of Lo/Ld interfaces, which may represent preferential sites for enzyme activation. Consistent with this, POVPC reduced sPLA2 activity through stabilization of ordered domains at both low and high cholesterol, while PGPC enhanced hydrolysis at high cholesterol. Importantly, PDPC-containing membranes attenuated sPLA2 activity and exhibited a protective effect against OxPC-induced enzymatic activation. Together, these findings identify membrane lateral organization as a key regulator of sPLA2 function and provide mechanistic insight into how oxidative stress can differentially modulate inflammatory lipid signaling depending on membrane composition. This work highlights membrane organization as an active determinant of enzyme activity and a potential target in pathologies associated with oxidative stress, including atherosclerosis, neuroinflammation, and metabolic disease.
    Keywords:  cholesterol; docosahexaenoic acid; lipid rafts; membrane lateral organization; oxidized phospholipids; sPLA2 activity
    DOI:  https://doi.org/10.3390/molecules31081298
  48. Mol Ther Oncol. 2026 Jun 18. 34(2): 201204
    How CAR T cells can be shielded from prostaglandin E2 signaling to enhance their therapeutic activity.
    Janina Dörr, David Andreu-Sanz, Sebastian Kobold.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201204
  49. Future Oncol. 2026 May 04. 1-8
    Impact of UGT1A1*28 polymorphism in patients with metastatic pancreatic ductal adenocarcinoma treated with NALIRIFOX in the NAPOLI 3 trial.
    Maen Abdelrahim, Gazala Khan, Hassan Hatoum, Alice Zervoudakis, Farshid Dayyani, Li Zhang, Jia Li, Fiona Maxwell, Eileen M O'Reilly, Zev A Wainberg, Andrea Bullock.
       AIMS: To evaluate the effect of UGT1A1*28 homozygosity on the safety profile of NALIRIFOX (liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in NAPOLI 3 (NCT04083235).
    METHODS: This pre-specified exploratory analysis evaluated safety outcomes by UGT1A1*28 status in patients with mPDAC receiving NALIRIFOX or gemcitabine plus nab-paclitaxel in NAPOLI 3. All patients receiving NALIRIFOX initiated liposomal irinotecan at the full starting dose.
    RESULTS: Among 749 treated patients, 83 were homozygous for UGT1A1*28. In the NALIRIFOX arm, grade ≥3 and serious treatment-emergent adverse events (TEAEs) related to liposomal irinotecan occurred in 61.5% and 33.3% of patients with homozygous UGT1A1*28 (n = 39), respectively, compared with 63.7% and 22.9% of patients with other genotypes (n = 328). The most common any-grade TEAEs for NALIRIFOX were diarrhea (59.0%), nausea (56.4%), vomiting (46.2%), and anemia (41.0%) in the homozygous group and diarrhea (71.6%), nausea (59.8%), vomiting (38.4%), and decreased appetite (38.1%) in the other genotypes group. Rates of TEAE-related treatment discontinuation and dose reduction/interruption in the NALIRIFOX arm were similar across genotypes.
    CONCLUSIONS: UGT1A1*28 homozygosity was not associated with increased toxicity in patients receiving NALIRIFOX in NAPOLI 3. These findings support the use of full NALIRIFOX dosing irrespective of UGT1A1*28 status.
    CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT04083235; EudraCT 2018-003585-14.
    Keywords:  Metastatic pancreatic ductal adenocarcinoma (mPDAC); NALIRIFOX; NAPOLI 3; SN-38; UGT1A1*28; homozygous; liposomal irinotecan
    DOI:  https://doi.org/10.1080/14796694.2026.2664776
  50. Cell Death Dis. 2026 May 07.
    Genetic mutations governing ferroptosis sensitivity and resistance: a precision approach to cancer therapy.
    Peyman Tabnak, Mohammad Ebrahimnezhad, Zanyar HajiEsmailPoor.
      Ferroptosis, an iron-dependent programmed cell death pathway driven by lipid peroxidation, offers a transformative approach to cancer therapy by exploiting unique cellular vulnerabilities. This comprehensive review elucidates the intricate molecular mechanisms of ferroptosis and their modulation by genetic mutations across diverse malignancies, including lung, hematological, liver, colorectal, breast, glioma, renal, pancreatic, thyroid, prostate, cervical, gastric, and melanoma. We delineate the critical functions of ferroptosis regulators, such as GPX4, system Xc⁻, and iron metabolism proteins, in orchestrating the delicate balance between oxidative damage and antioxidant protection. The study further examines how oncogenic mutations in genes like EGFR, KRAS, TP53, KEAP1, and IDH1 reshape ferroptosis susceptibility or resistance through alterations in metabolic pathways, redox homeostasis, and tumor microenvironment interactions. By highlighting mutation-specific sensitivities, this work underscores the potential of ferroptosis-targeted strategies to surmount therapeutic resistance, synergize with conventional treatments like chemotherapy and immunotherapy, and drive precision oncology forward, paving the way for enhanced clinical outcomes across a broad spectrum of cancers.
    DOI:  https://doi.org/10.1038/s41419-026-08796-w
  51. Sci Adv. 2026 May 08. 12(19): eadu8849
    PARP2 deficiency impairs pancreatic cancer progression by promoting genomic instability and antitumor immunity.
    Neus Martínez-Bosch, Noemí Manero-Rupérez, Núria Vázquez-Bellón, Bennett Nickell-Hernández, Cristina Ventura-Blanch, Nura Lutfi, Carmen G Lechuga, Carlos Martínez, Mireia Moreno, Coral Ampurdanés, Etna Abad, Mar Iglesias, María Muñoz-Escribano, Ana Janic, Meritxell Rovira, Carmen Guerra, Gabriel A Rabinovich, José Yélamos, Pilar Navarro.
      Pancreatic cancer represents one of the most lethal tumors, characterized by an immunosuppressive microenvironment and a lack of cytotoxic immune cell infiltrates, which confer resistance to immunotherapy. Here, we demonstrate that deletion of poly(ADP-ribose) polymerase 2 (PARP2) in a Myc-driven mouse model of pancreatic cancer delays tumor progression and increases survival. Mechanistically, PARP2 loss induces enrichment of pathways associated with genomic instability and replicative stress, leading to increased γH2AX, chromosomal instability, and micronuclei accumulation. In addition to these tumor-intrinsic effects, PARP2 deletion reshapes the tumor microenvironment, promoting infiltration of cytotoxic T and natural killer cells while reducing immunosuppressive cell populations, enhancing antitumor cytotoxicity. These findings are recapitulated in a KrasG12D-driven orthotopic pancreatic ductal adenocarcinoma model. Collectively, our data support selective PARP2 inhibition as a promising therapeutic strategy for pancreatic cancer by impairing genome integrity and boosting antitumor immune response, thereby opening potential avenues for combating this devastating disease.
    DOI:  https://doi.org/10.1126/sciadv.adu8849
  52. Gastroenterology. 2026 May 06. pii: S0016-5085(26)06818-6. [Epub ahead of print]
    Neutrophil-Driven Trogocytosis in PDAC Liver Metastases Restrains Immunosuppressive Macrophage Polarization and Limits Metastatic Progression.
    Larissa Belz, Dominic van den Heuvel, Badr Kilani, Alejandro Martinez-Navarro, Anastassia Akhalkatsi, Markus Joppich, Yinfeng Zhu, Qiongjie Ding, Jinlong Wan, Julia Stermann, Julia Winterhalter, Denise Messerer, Anna Titova, Sanjana Balaji, Santoshi Giri, Luke Eivers, Sebastian Widholz, Stefanie Bärthel, Elisabeth Raatz, Dieter Saur, Kirsten Lauber, Georg Beyer, Julia Mayerle, Steffen Ormanns, Michael Guenther, Steffen Massberg, Hellen Ishikawa-Ankerhold, Konstantin Stark.
       BACKGROUND & AIMS: Pancreatic Ductal Adenocarcinoma (PDAC) metastasizes early and frequently to the liver, limiting therapeutic options and resulting in poor prognosis. Neutrophils are key immune players in cancer progression, yet their role in PDAC liver metastases remains unclear. This study investigates how neutrophils influence hepatic macrophages and modulate the immune landscape in the metastatic microenvironment using intravital calcium imaging and single-cell RNA sequencing (scRNA-seq).
    METHODS: Intravital microscopy was used to monitor neutrophil behavior and interactions within the metastatic niche. We employed intravital calcium imaging in LysMcre-PCG5-tdt mice to visualize real-time immune cell interactions and their functional impact in a PDAC metastasis model. To dissect the effect of neutrophils on the immune landscape, we performed single-cell RNA sequencing of liver-infiltrating leukocytes in tumor-bearing mice.
    RESULTS: Intravital calcium imaging revealed that neutrophils are recruited to hepatic metastases by CCL2/CCL5, where they take up tumor cell fragments via trogocytosis and subsequently present these tumor fragments to hepatic macrophages. This neutrophil-driven immunomodulation was abolished upon neutrophil depletion, resulting in a permissive tumor-promoting macrophage phenotype. Single-cell RNA sequencing identified distinct macrophage subpopulations, demonstrating that neutrophils suppress the development of immunosuppressive macrophages by C3-dependent signaling and enhance anti-tumor signaling pathways.
    CONCLUSIONS: This study provides in vivo evidence of neutrophil-macrophage crosstalk in PDAC liver metastases and highlights the functional consequences of neutrophil depletion. By integrating intravital calcium imaging with single-cell RNA sequencing, we uncover a previously unrecognized mechanism of neutrophil-driven immunomodulation, emphasizing the potential for therapeutic strategies targeting neutrophil-macrophage interactions in metastatic PDAC.
    Keywords:  CCL2; CCL5; Innate Immune cells; tumor immunology
    DOI:  https://doi.org/10.1053/j.gastro.2026.04.021
  53. Biomaterials. 2026 Apr 30. pii: S0142-9612(26)00280-2. [Epub ahead of print]334 124256
    Hide-and-seek molecular navigator targets tumor cell surface thiols by programmable disulfide exchange.
    Pengwen Chen, Guanghao Hu, Wenqian Yang, Yuki Nakashima, Zhining Xu, Yiyi Yang, Soichiro Kondo, Xiwen Chen, Sosuke Takasugi, Ervin Kovács, Katsuhito Fujiu, Horacio Cabral.
      Metabolism dysregulation induces distinct thiol profiles between cancer and healthy cells, offering an attractive therapeutic target. However, systemically targeting cancer-specific thiols remains challenging due to the widespread presence of these groups in the physiological environment. Here, we design a molecular navigator (MONA) with spatiotemporally programmable thiol-reactivity to target the thiols on cancer cells upon intravenous injection. MONA operates through a bioresponsive "Hide-and-Seek" mechanism based on tunable disulfide exchange across biological compartments. In the "Hide" phase, MONA circulates stealthily through rapid conjugation with endogenous albumin via disulfide bonding. In the "Seek" phase, albumin facilitates MONA transcytosis into tumors, where elevated glutathione levels trigger disulfide exchange, releasing MONA to multivalently engage with thiols on cancer cells. When conjugated with a photosensitizer, MONA induces cancer cell membrane disruption upon light irradiation, enabling potent phototherapy. This approach leads to complete tumor regression and systemic abscopal effects in an immunosuppressive murine breast cancer model. These findings highlight MONA as a powerful strategy for precise thiol-targeted cancer therapy.
    Keywords:  Albumin hitchhiking; Antitumor therapeutics; Disulfide exchange; Drug delivery; Immunogenic cell death
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124256
  54. Cell Metab. 2026 May 05. pii: S1550-4131(26)00109-9. [Epub ahead of print]38(5): 833-834
    Fasting opens a metabolic window that favors anti-tumor immunity.
    Ling Cai, Tao Dai.
      Short-term fasting reshapes the metabolic landscape of the tumor microenvironment, creating a transient window of altered nutrient availability that cytotoxic CD8⁺ T cells can exploit. Chen and colleagues report that intratumoral isoleucine accumulation during fasting supports T cell effector programs, enhancing responses to immune checkpoint blockade in mice and humans.
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.015
  55. bioRxiv. 2026 Apr 23. pii: 2026.04.23.720363. [Epub ahead of print]
    Dual Pathways of Extracellular ATP Action in Cancer Cells: Purinergic Signaling-Driven Senescence and Macropinocytic ATP Internalization.
    Nicole Stone, Ryan Ward, Lindsey Bachmann, Subhodip Adhicary, Corinne M Nielsen, Nikunj Mehta, Yunsheng Li, Haiyun Zhang, Jingwen Song, Sam Prinz, Stephen Chang, Dennis Roberts, Stephen Bergmeier, Pratik Shriwas, Xiaozhuo Chen.
       Background: Opportunistic nutrient uptake is a hallmark of cancer metabolism. Cancer cells upregulate macropinocytosis to acquire extracellular nutrients to support growth and stress adaptation. We previously showed that extracellular ATP (eATP) is internalized by macropinocytosis and promotes multiple cancer phenotypes. Here, we tested whether eATP uptake is prevalent across cancers and whether eATP also induces senescence through purinergic receptor (PR) signaling.
    Methods: Intracellular ATP (iATP) levels were measured following eATP exposure across multiple cancer cell lines. eATP internalization was visualized in vitro and in vivo using a non-hydrolyzable fluorescent ATP analog together with high-molecular-weight dextran as a macropinocytosis marker. Senescence was quantified using three SA-β-galactosidase assays and flow cytometry. Pharmacologic inhibitors of macropinocytosis and purinergic receptors were used to define pathway dependence. Combination treatments with the glucose transporter inhibitor DRB18 and the senolytic navitoclax were evaluated for antiproliferative effects.
    Results: eATP produced dose- and time-dependent increases in iATP across diverse cancer cell types. Imaging demonstrated widespread macropinocytic internalization of ATP in vitro and in tumor xenografts. eATP induced senescence in NSCLC cells, confirmed by multiple β-gal assays and flow cytometry. PR inhibition significantly reduced senescence, whereas macropinocytosis inhibition had minimal effect on senescence induction.
    Conclusions: eATP acts through dual pathways in cancer cells: macropinocytic internalization that elevates iATP and PR signaling that drives senescence. Targeting metabolic uptake together with senolytic therapy may offer a novel anticancer strategy.
    DOI:  https://doi.org/10.64898/2026.04.23.720363
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