bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–07–26
27 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Precision Medicine in Pancreatic Cancer: Targeting KRAS and Beyond.
  2. PLA2G2F suppresses ferroptosis through phospholipid remodeling.
  3. Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
  4. Global cellular responses to lysosomal damage.
  5. A comprehensive proteomic dataset of secretomes from primary pancreatic cancer cell cultures.
  6. Engineered probiotic Bifidobacterium for tumor-targeted pancreatic cancer therapy.
  7. Ferroptosis at the intersection of metabolism and immunity in pancreatitis and pancreatic cancer.
  8. LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
  9. Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across heart, liver, kidney, and muscle.
  10. Molecular dynamics perspectives on annexin-mediated plasma membrane repair: From recruitment to membrane mechanics.
  11. Breaking the RAS Barrier in Pancreatic Cancer.
  12. Cholesteryl Esters Modulate Lipid Droplet Rigidity and Monolayer Organization during Liver Cancer Progression.
  13. Cell-size heterogeneity acts as a regime-dependent mechanical switch for collective migration.
  14. Cytostatic autophagy: an underappreciated form of autophagy and its ramifications in cancer.
  15. New hope in the fight against cachexia - cancer's deadly co-conspirator.
  16. Lipids in ovarian cancer ascites impair T cell activation by disrupting TCR dynamics.
  17. Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
  18. Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.
  19. Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
  20. Directed migration of cancer cells: a systems biophysics perspective.
  21. Daraxonrasib in Advanced RAS-Mutated Pancreatic Cancer. Reply.
  22. A lysosome-targeted ultra-sensitive viscosity probe for monitoring viscosity alterations during chemotherapy.
  23. Dynamic dimer-of-dimers architecture defines Mg2+ transport in human CNNM4.
  24. Growth factor supportive care for chemotherapy-induced neutropenia suppresses antitumour immunity in checkpoint blockade-responsive pancreatic cancer.
  25. Identifying lipid-protein interactomes with functional lipid probes.
  26. Novel antioxidant effects of deuterated polyunsaturated fatty acids against lipid peroxidation in cell membranes: hypothesis paper.
  27. Dual-MEK Inhibitor Atebimetinib Displays Broad Activity in RAS- and RAF-Mutant Tumors via Deep Cyclic Inhibition and Resisting RAF-Bypass.
  1. Target Oncol. 2026 Jul 20.
    Precision Medicine in Pancreatic Cancer: Targeting KRAS and Beyond.
    Hendrik Schürmann, Wungki Park, Grainne M O'Kane, Carolina Sciortino, Monica Niger, Maximilian Reichert, Kenneth P Olive, Ina Pretzell, C Benedikt Westphalen.
      For the past decades, chemotherapy constituted the therapeutic foundation in advanced or metastatic pancreatic cancer. Despite significant advances in the molecular understanding, translation into tangible patient benefit has remained modest. Until recently, mutant KRAS, the dominant oncogenic driver, was considered undruggable, and only a small subgroup of patients potentially benefited from targeted therapies. With the emergence of KRAS inhibitors, most patients with pancreatic cancer in theory qualify for targeted therapeutics. Final results from the RASolute 302 trial showed clinically meaningful activity of RAS inhibition in patients with metastatic pancreatic cancer and paved the way for approval. Ongoing preclinical and coclinical studies have documented both intrinsic and acquired mechanisms of resistance to KRAS inhibition. Given the cellular plasticity seen in pancreatic cancer, the identification and anticipation of resistance mechanisms will be critical to exploit emerging therapeutic vulnerabilities through novel combination strategies. In view of the increasing number of trials and the growing body of evidence for targeted therapies, pancreatic cancer is entering a transitional phase in which precision oncology strategies must be redefined beyond rare molecular subgroups. In this review, we will briefly revisit targeted therapeutic approaches in pancreatic cancer to then discuss the clinical implications of genomic and transcriptomic heterogeneity in KRAS-mutant and KRAS wild-type disease. We will outline how our expanding biological insights into pancreatic cancer could inform combination and sequential therapeutic approaches.
    DOI:  https://doi.org/10.1007/s11523-026-01236-x
  2. Nat Struct Mol Biol. 2026 Jul 22.
    PLA2G2F suppresses ferroptosis through phospholipid remodeling.
    Yingying Hu, Joleen Csuka, Presha Rajbhandari, Penghsuan Huang, Nicholas Carbone, Deguang Liang, Wei Gu, Alban Ordureau, Brent R Stockwell, Xuejun Jiang.
      Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation, and it has emerged as a potential therapeutic vulnerability of cancer. Here we identify the secretory phospholipase PLA2G2F (phospholipase A2 group IIF) as a ferroptosis suppressor in bladder cancer and elucidate its regulation and mechanism of action. PLA2G2F functions through an intracellular mechanism by localizing to the endoplasmic reticulum to inhibit ferroptosis. Our genetic and pharmacological analyses reveal that peroxisome proliferator-activated receptor γ (PPARG), a nuclear hormone receptor and transcription factor previously implicated in ferroptosis regulation, upregulates PLA2G2F and that PPARG-mediated ferroptosis resistance is largely dependent on PLA2G2F in bladder cancer. Further, lipidomic profiling suggests that PLA2G2F preferentially acts on ether-linked phospholipids containing polyunsaturated fatty acids, thereby reducing the pool of peroxidation-prone polyunsaturated fatty acid-containing phospholipids. Together, our findings establish PLA2G2F as an endoplasmic reticulum-resident ferroptosis suppressor regulated by PPARG and show that inhibiting PPARG signaling or PLA2G2F activity can sensitize bladder cancer cells to ferroptosis induction.
    DOI:  https://doi.org/10.1038/s41594-026-01830-7
  3. Dev Cell. 2026 Jul 21. pii: S1534-5807(26)00240-6. [Epub ahead of print]
    Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.
    Adrien Grimont, David J Falvo, Whitney J Sisso, Francisco Santos, Christopher W Chan, Paul Zumbo, William B Fall, Katherine Ferrick, Grace Pan, Megan Cleveland, Tomer M Yaron-Barir, Alexa Osterhoudt, Yinuo Meng, Maria Paz Zafra, Andre F Rendeiro, Erika Hissong, Rhonda K Yantiss, Doron Betel, Mark A Magnuson, Steven D Leach, Anil K Rustgi, Lukas E Dow, Rohit Chandwani.
      Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic ductal adenocarcinoma. How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement Ptf1a-tdTomato mice and multiple KRAS mutants across several genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRASG12D co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRASG12R/V cannot sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. Specifically, KRASG12R/V mutants fail to invoke robust EGFR, AKT, and RAC1/VAV1 signaling and to license Pou2f3 and Vav1 in chromatin, such that only constitutive AKT activation is sufficient to rescue the tumorigenic potential of KRASG12Rin vivo. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to deciphering mutation-specific oncogenic trajectories and directing the implementation of KRAS-directed therapeutics.
    Keywords:  EGFR; G12R; KRAS; RAC1; VAV1; acinar-ductal metaplasia; epigenetic reprogramming; inflammation; lineage reversion; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.devcel.2026.06.016
  4. Curr Biol. 2026 Jul 20. pii: S0960-9822(26)00655-X. [Epub ahead of print]36(14): R807-R820
    Global cellular responses to lysosomal damage.
    Jingyue Jia.
      Lysosomes are membrane-bound organelles that orchestrate a wide range of cellular processes, including degradation, metabolism, signaling, gene regulation and quality control, while interacting with other organelles, thereby profoundly shaping cellular homeostasis and fate. Lysosomal membrane integrity is highly vulnerable to a broad spectrum of physiological and pathological insults, acting as both a cause and a consequence of diverse human conditions, including neurodegeneration, cancer, infectious disease and aging. Understanding the mechanisms by which cells respond to lysosomal damage is therefore of critical importance. Recent studies have revealed that cells deploy sophisticated damage response mechanisms locally to repair, remove, and replace damaged lysosomes. In contrast, how local lysosomal damage triggers global cellular responses is only beginning to be understood. This review summarizes recent conceptual advances in global cellular responses to lysosomal damage, encompassing translational, metabolic and transcriptional adaptations, and highlights their crucial roles in restoring cellular homeostasis and shaping outcomes in health and disease.
    DOI:  https://doi.org/10.1016/j.cub.2026.05.050
  5. Sci Data. 2026 Jul 20.
    A comprehensive proteomic dataset of secretomes from primary pancreatic cancer cell cultures.
    Julie Roques, Alex Chauvin, Nicolas Fraunhoffer, Dinah Ratovonindrina, Brice Chanez, Odile Gayet, Stéphane Audebert, Luc Camoin, Juan Iovanna, Nelson Dusetti, Philippe Soubeyran.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with poor prognosis and limited therapeutic options. Early biomarkers for the detection and prediction of treatment response are sorely lacking. The tumour secretome, the set of proteins released by cancer cells, represents a promising source of biomarkers and provides insights into tumour biology, as these factors may be detectable in blood and suitable for non-invasive monitoring. However, most secretome studies have relied on established cell lines or mouse models, poorly reflecting human tumour heterogeneity. To address this gap, we generated a comprehensive proteomic dataset of secretomes from 48 low-passage, treatment-naïve, patient-derived primary PDAC cultures, which retain the molecular and phenotypic features of their tumours of origin. Across samples, we identified 4,204 proteins, including 793 shared by all cultures. Annotation showed that most of these proteins matched extracellular vesicle contents and canonical secreted proteins that may reach the circulation. Consequently, this dataset provides a valuable resource for the identification of circulating biomarkers and for comparative analyses of PDAC secretomes.
    DOI:  https://doi.org/10.1038/s41597-026-07902-z
  6. Sci Adv. 2026 Jul 24. 12(30): eadz1388
    Engineered probiotic Bifidobacterium for tumor-targeted pancreatic cancer therapy.
    Jaehyun Lee, Kaiting Yang, Christina A Nowicki, Wei Liu, Kangdi Li, Emile Naccasha, Zhichen Sun, Yang-Xin Fu, Hua Liang, Ralph R Weichselbaum, Mark Mimee.
      Pancreatic ductal adenocarcinoma (PDAC) presents a substantial challenge due to its resistance to cancer treatments. This limited efficacy is, in part, attributed to the immunosuppressive tumor microenvironment (TME), which impairs effector T (Teff) cell activity. Interleukin-2 (IL-2) is a key cytokine for T cell activation, but its therapeutic use is limited by a short half-life, systemic toxicity, and regulatory T (Treg) activation. To address this limitation, we engineered Bifidobacterium longum, a probiotic obligate anaerobe that selectively colonizes the TME, to continuously secrete Super-mutant IL-2 (SumIL-2), an engineered IL-2 variant that preferentially activates Teff cells over Treg cells, thereby delivering SumIL-2 selectively to the tumor (BifidoSumIL-2). Systemic administration of BifidoSumIL-2 significantly suppressed tumor growth in both subcutaneous tumors and orthotopic PDAC in mice, inducing an improved Teff/Treg ratio. Combining BifidoSumIL-2 with chemotherapy, radiation, and immunotherapy further restrained orthotopic PDAC growth, highlighting its therapeutic potential for difficult-to-treat cancers like PDAC.
    DOI:  https://doi.org/10.1126/sciadv.adz1388
  7. Semin Immunol. 2026 Jul 24. pii: S1044-5323(26)00036-9. [Epub ahead of print]83 102049
    Ferroptosis at the intersection of metabolism and immunity in pancreatitis and pancreatic cancer.
    Fangquan Chen, Xiutao Cai, Ruirui Liang, Rui Kang, Jiao Liu.
      Ferroptosis links cellular metabolism to immune regulation. Beyond its role as an iron-dependent form of regulated cell death, ferroptosis generates signals, including oxidized lipids, iron metabolites, and damage-associated molecular patterns, that influence inflammatory and immune responses. The pancreas is particularly susceptible to ferroptotic stress because of its high metabolic demand and close integration with immune and stromal networks. In pancreatitis, ferroptosis translates metabolic injury into innate immune activation, contributing to sterile inflammation and tissue damage. In pancreatic cancer, ferroptotic vulnerabilities can be exploited therapeutically, yet ferroptosis-associated signals may also support immune suppression, immune evasion, and treatment resistance. These findings suggest that ferroptosis functions as an immunometabolic checkpoint rather than simply a cell death program. Here, we discuss how ferroptosis shapes immune responses in pancreatitis and pancreatic cancer and examine the factors that determine whether it promotes inflammation, antitumor immunity, or immune tolerance. We also review ferroptosis-targeted therapies and the challenges associated with their clinical application.
    Keywords:  DAMPs; Ferroptosis; Immunity; Pancreatic cancer; Pancreatitis
    DOI:  https://doi.org/10.1016/j.smim.2026.102049
  8. Cell Death Dis. 2026 Jul 20. pii: 649. [Epub ahead of print]17(1):
    LSD1-GLS2 axis drives subtype-specific chemoresistance in pancreatic cancer through glutaminolysis reprogramming.
    Zhefang Wang, Qiu Huang, Jiangang Zhao, Zicheng Lyu, Feng Ju, Bo You, Jie Wang, Qiongzhu Dong, Margarete Odenthal, Alexander Quaas, Kalliope N Diakopoulos, Hana Algül, Maximilian Reichert, Christiane J Bruns, Yue Zhao.
      Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09075-4
  9. Hum Cell. 2026 Jul 19. pii: 112. [Epub ahead of print]39(8):
    Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across heart, liver, kidney, and muscle.
    Julia Osaki, Yomogi Shiota, Ikumi Fujita, Kazuyoshi Yanagihara, Tadashi Kondo.
      Cancer cachexia is a debilitating systemic syndrome that affects a substantial proportion of patients with advanced malignancy and is associated with impaired treatment tolerance, reduced quality of life, and increased mortality. While skeletal muscle wasting is a defining clinical feature, cachexia involves coordinated dysfunction across multiple organs, yet it remains unclear whether cachexia imposes a unified, body-wide transcriptional program or primarily induces organ-specific responses. Here, we leveraged an isogenic xenograft model derived from human duodenal neuroendocrine carcinoma in which the cachexia-inducing subline AkuNEC was established through in vivo serial passaging from the parental, largely non-cachexia-inducing line TCC-NECT-2. We performed bulk RNA sequencing of skeletal muscle, liver, kidney, and heart from cachectic AkuNEC-bearing mice, non-cachectic TCC-NECT-2-bearing mice, and uninoculated controls. Differential expression analyses identified organ-dependent sets of transcripts associated with cachexia. However, unsupervised analyses of global expression patterns consistently showed that tissue identity dominated transcriptome structure and samples did not segregate by cachexia status. In addition, comparisons of tumor-bearing vs uninoculated controls revealed broadly similar transcriptional shifts for AkuNEC and TCC-NECT-2 within each organ. Together, these data indicate that cachexia-associated transcriptional changes are present but remain modest relative to dominant tissue-specific programs at the whole-transcriptome level. The AkuNEC/TCC-NECT-2 system provides a controlled platform for future studies incorporating cell-type-resolved, spatial, and multi-omic approaches to delineate the mechanisms linking tumor evolution to multi-organ remodeling in cancer cachexia.
    Keywords:  AkuNEC; Cancer cachexia; Duodenal neuroendocrine carcinoma; Heart; Kidney; Liver; Multi-organ dysfunction; RNA-seq; Skeletal muscle; TCC–NECT-2; Transcriptomics; Xenograft
    DOI:  https://doi.org/10.1007/s13577-026-01412-1
  10. Biochim Biophys Acta Biomembr. 2026 Jul 23. pii: S0005-2736(26)00063-5. [Epub ahead of print]1868(4): 184560
    Molecular dynamics perspectives on annexin-mediated plasma membrane repair: From recruitment to membrane mechanics.
    Ali Asghar Hakami Zanjani.
      This mini-review examines how molecular dynamics simulations reshape the view of annexin-mediated plasma membrane repair from simple recruitment to coupled protein-membrane states. Molecular dynamics simulations show that annexin-induced curvature is shaped by oligomerization, cholesterol, and anionic lipid chemistry, while engineering normally non-trimerizing annexin A3 into a trimer-forming state demonstrates that curvature generation alone does not ensure repair competence. Membrane-active perturbants such as trifluoperazine further suppress repair by altering bilayer thickness, lipid packing, phosphatidylserine mobility, and annexin binding. These findings shift the question from whether annexins arrive to how protein-membrane states generate repair-relevant remodeling.
    Keywords:  Annexins; Membrane curvature; Membrane mechanics; Molecular dynamics simulations; Plasma membrane repair; Protein–membrane interactions
    DOI:  https://doi.org/10.1016/j.bbamem.2026.184560
  11. N Engl J Med. 2026 Jul 23. 395(4): 400-401
    Breaking the RAS Barrier in Pancreatic Cancer.
    Shivan Sivakumar.
      
    DOI:  https://doi.org/10.1056/NEJMe2606948
  12. Langmuir. 2026 Jul 22.
    Cholesteryl Esters Modulate Lipid Droplet Rigidity and Monolayer Organization during Liver Cancer Progression.
    Oluwatoyin Campbell, Cecilia Leal, Viviana Monje.
      In mammalian cells, lipid monolayers support the integrity of lipid droplets (LDs), organelles that function as storage sites for neutral lipids. Liver-targeting illnesses such as liver cancer interrupt normal LD metabolism and prompt changes in the chemical content of these organelles, which can have effects on the structural and organizational behavior of the lipids. In LDs, liver cancer induces concentric crystalline phases of cholesteryl esters (CEs) and triglycerides near the neutral lipid-monolayer interface, which become more pronounced as the CE concentration increases. Yet, there is little known about how this phenomenon may link to the persistence of undigested LDs in liver cancer patients. To shed light on this, all-atom molecular dynamics simulations were used to model LD micropipette aspiration experiments and gain insights into the effect of CE concentration on partitioning, structural, and mechanical properties of LDs. We successfully modeled micropipette aspiration by applying constant surface tension laterally, which stretched lipid bilayers and monolayers as the magnitude increased. The results show increased phospholipid packing due to the insertion of CE fatty tails into the monolayer. Increasing CE concentration induces a nonlinear change in surface packing defects on the LDs, notable rigidification, and stiffness. Taken together, these insights improve our understanding of the effect of CE abundance on the physical properties at the LD monolayer-core interface.
    DOI:  https://doi.org/10.1021/acs.langmuir.6c02683
  13. Biophys J. 2026 Jul 20. pii: S0006-3495(26)00517-5. [Epub ahead of print]
    Cell-size heterogeneity acts as a regime-dependent mechanical switch for collective migration.
    Xiangdong Kong, Xinyuan Wu, Mingyue Wang, Yuanyuan Liu, Chao Fang.
      Cell-size heterogeneity is ubiquitous in epithelial tissues, yet the fundamental physical principles governing its impact on collective migration remain elusive. Here, we show that size heterogeneity acts as a regime-dependent mechanical switch: it enhances collective motility in solid-like tissues while strongly suppressing migration in fluidized ones. This reversal arises from a previously unrecognized energetic hierarchy that governs microscopic topological remodeling. By systematically quantifying the work required for cellular neighbor exchanges, we demonstrate that size diversity reshapes the tissue energy landscape. In heterogeneous tissues, larger cells function as mechanically constrained anchors that elevate local rearrangement barriers, stabilizing the tissue against topological fluctuations. Crucially, these emergent energetic constraints either compete with or reinforce shape-based structural changes depending on the mechanical state, dictating the overall rate of tissue remodeling. Together, our results establish a unified physical framework linking microscale size heterogeneity to the fundamental energetic cost of cell rearrangements, and suggest that cell-size distribution serves as an intrinsic tunable parameter that dictates the epithelial mechanical property and migratory potential across diverse physiological contexts.
    DOI:  https://doi.org/10.1016/j.bpj.2026.07.022
  14. Autophagy. 2026 Jul 24.
    Cytostatic autophagy: an underappreciated form of autophagy and its ramifications in cancer.
    Ahmed M Elshazly, Aya A Elzahed, Shady Allam, Daniel J Klionsky, Senthil K Radhakrishnan, David A Gewirtz.
      Macroautophagy/autophagy is a well-established homeostatic mechanism that contributes to the integrity of multiple regulatory biological activities including but not limited to the gastro-intestinal tract and cognitive integrity. Autophagy also plays a central role in tissue regeneration, metamorphosis and development whereas defects in autophagy are associated with a wide range of disorders including metabolic diseases such as diabetes, organ pathophysiologies including liver, lung and heart disease, cancer, and microbial infection. In the field of cancer therapy, most research efforts have focused on cytoprotective autophagy, with substantial preclinical and clinical studies designed to interrogate the outcomes of pharmacologically (or genetically in preclinical work) inhibiting autophagy to enhance the efficacy of chemotherapeutic agents. There is lesser but nevertheless robust evidence for the cytotoxic function of autophagy while our laboratory and a few others have identified the nonprotective form of this cellular response. However, cytostatic autophagy, a distinct functional outcome of autophagy characterized by sustained proliferative arrest, has remained relatively underexplored. Cytostatic autophagy can be defined as a cellular condition in which autophagy activation coincides with durable proliferative arrest, and in which genetic or pharmacological inhibition of autophagy relieves the growth-arrest phenotype without inducing overt cytotoxicity. In this review, we provide the first comprehensive synthesis of the scientific literature addressing cytostatic autophagy, tracing its historical development and consolidating the experimental evidence that led to its current conceptual definition. We further discuss the molecular mechanisms underlying cytostatic autophagy, including the selective degradation of key cell-cycle regulators and the interplay between autophagy and senescence-associated signaling pathways.
    Keywords:  Autophagy; cancer; cell cycle; cytostasis; senescence
    DOI:  https://doi.org/10.1080/15548627.2026.2709937
  15. Nature. 2026 Jul;655(8124): 836-838
    New hope in the fight against cachexia - cancer's deadly co-conspirator.
    Amber Dance.
      
    Keywords:  Cancer; Drug discovery; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-02228-7
  16. Nat Metab. 2026 Jul;8(7): 1508-1527
    Lipids in ovarian cancer ascites impair T cell activation by disrupting TCR dynamics.
    Erica G Brown, Ewoud B Compeer, Zhiyang Gan, Andre R Kelly, Alexander A Shestov, Laura Córdoba-Espejo, Mitchell T Evans, Alan Y Liu, Noelle H Naughton, Tanay S Parnaik, Jemma H Larson, Bruce R Blazar, Caroline R Bartman, Joshua D Rabinowitz, Michael L Dustin, Daniel J Powell, Roddy S O'Connor.
      T cell-based therapies have limited success against ovarian cancer for poorly understood reasons. Here we show that lipids in ovarian cancer ascites fluid disrupt nanoscale T cell receptor dynamics-driven T cell activation. T cells stimulated in ascites of patients with ovarian cancer have an altered lipid profile, including changes in phosphatidylcholine (PC) and phosphatidylethanolamine content, and disrupted membrane properties. Using untargeted lipidomics, we reveal which lipid species are consumed by T cells in ascites and show that 18:0-18:2 PC impairs T cell activation at physiological concentrations. Mechanistically, we uncover that lipids in ascites, including 18:0-18:2 PC, disrupt nanoscale T cell receptor clustering in immunological synapses. Importantly, pre-activated T cells overcome these lipid-induced barriers, highlighting a promising strategy to enhance adoptive T cell-based therapies for ovarian cancer. These findings provide mechanistic insights into lipid-mediated immune suppression in the tumour microenvironment and an actionable strategy to overcome these barriers.
    DOI:  https://doi.org/10.1038/s42255-026-01557-1
  17. Nat Metab. 2026 Jul 23.
    Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
    Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.
      Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.
    DOI:  https://doi.org/10.1038/s42255-026-01578-w
  18. Nat Commun. 2026 Jul 18.
    Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.
    Xinxin Liu, Zhihua Huang, Bohan Yang, Yimeng Du, Yixin Sun, Enkui Zhang, Xiaofeng Kang, Chunyuan Xue, Kai Chen, Yongsu Ma, Xiaodong Tian, Xiaojie Xu, Yinmo Yang.
      Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is partly driven by pathological stromal remodeling, yet the underlying mechanisms remain poorly understood. Here, we show that gemcitabine treatment induces tumor cell senescence and activates cancer-associated fibroblasts via the senescence-associated secretory phenotype, leading to progressive fibrotic matrix stiffening. This biomechanical reprogramming engages the mechanosensitive ion channel Piezo1, triggering metabolic rewiring that renders BRG1-positive tumor cells increasingly dependent on NRF2-mediated antioxidant defenses. Piezo1 signaling promotes NRF2 nuclear translocation and its chromatin-remodeling cooperation with BRG1, thereby upregulating SLC7A11-dependent antioxidant programs and suppressing ferroptosis. Notably, the combination of the senolytic agent ABT-263 with the ferroptosis inducer Erastin effectively dismantles BRG1-NRF2-driven gemcitabine resistance, alleviates stromal fibrosis, enhances T-cell infiltration, and suppresses tumor growth in vivo. This senolytic-ferroptosis approach exploits metabolic vulnerabilities in chemotherapy-aged PDAC and provides a mechanistic rationale for stroma-targeted combination therapies.
    DOI:  https://doi.org/10.1038/s41467-026-75772-5
  19. Nat Cell Biol. 2026 Jul 20.
    Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
    Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song.
      Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia-reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia-reoxygenation. This stress-responsive ITM2C-MIRO2-MFF-DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria-lysosome communication in mediating lysosomal quality control during ischaemia-reperfusion and related stresses.
    DOI:  https://doi.org/10.1038/s41556-026-02010-x
  20. Front Cell Dev Biol. 2026 ;14 1832990
    Directed migration of cancer cells: a systems biophysics perspective.
    Andrew Mugler, Bumsoo Han.
      Directed migration of cancer cells is crucial to tumor progression, including tumorigenesis and metastasis. During migration, cancer cells encounter complex environmental cues and must process these signals to determine their migration direction. These cues include chemical, mechanical, and fluidic signals that vary across space and time. Although cancer cell migration has been extensively studied and many molecular regulators and signaling pathways have been identified, this molecular knowledge alone is often insufficient to predict migratory behavior in the highly heterogeneous tumor microenvironment. In this perspective, we present a systems biophysics framework that views directed migration as an information-processing problem constrained by the physics of cellular motion. Within this framework, a migrating cancer cell can be conceptualized as an integrated system composed of interacting subsystems responsible for information acquisition, information processing, and actuation. These subsystems collectively enable cells to sense environmental cues, process competing signals, and generate directed movement. Using a combination of biophysical analysis, experiments, and theoretical modeling, we discuss recent efforts to quantify fundamental sensing limits, characterize individual and collective information acquisition, investigate the capacity of cellular signal-processing machinery, and identify physical constraints governing migration accuracy and persistence. We further describe how minimal theoretical models and reverse-engineering approaches can reproduce key features of cellular decision-making, including the use of logic-gate-like behavior to process multiple environmental cues. Together, these studies illustrate how systems-level biophysical analysis can provide predictive insights into how cancer cells navigate complex microenvironments and may help establish a unified framework for understanding directed migration across diverse cellular systems.
    Keywords:  chemotaxis; epidermal growth factor (EGF); rheotaxis; transforming growth factor beta (TGF-β); tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1832990
  21. N Engl J Med. 2026 Jul 23. pii: 10.1056/NEJMc2607459#sa2. [Epub ahead of print]395(4): 414
    Daraxonrasib in Advanced RAS-Mutated Pancreatic Cancer. Reply.
    Brian M Wolpin, David S Hong.
      
    DOI:  https://doi.org/10.1056/NEJMc2607459
  22. Smart Mol. 2026 Jun 10. e70070
    A lysosome-targeted ultra-sensitive viscosity probe for monitoring viscosity alterations during chemotherapy.
    Haoyang Song, Hui Bian, Lei Liu, Gahyeon Park, Bingqing Sun, Qiongzheng Hu, Juyoung Yoon.
      Lysosomal viscosity is a key biomarker of cancer progression and chemotherapy response, but real-time, precise monitoring remains challenging. To address this challenge, we develop a novel chemosensing platform based on a molecular rotor architecture for specific, dynamic detection of lysosomal viscosity. The platform operates via an "off-on" switching mechanism: in low-viscosity environments, rapid rotor rotation through the twisted intramolecular charge transfer effect quenches fluorescence; in high-viscosity conditions, restricted rotation triggers strong emission, enabling an ultra-sensitive and selective response. Using systematic molecular engineering and screening within this platform, the probe PMA-H is identified as the optimal candidate, demonstrating a remarkable 187-fold fluorescence enhancement in response to viscosity (from 0.54 to 1410 cP), excellent environmental stability with minimal interference from pH, polarity, or biomolecules, and precise lysosomal targeting. Subsequently, PMA-H is employed to track lysosomes in HeLa cells, and it reveals alterations in lysosomal viscosity, morphology, and abundance during apoptosis, ferroptosis, cuproptosis, and zinc-induced cell death. In general, this platform allows real-time tracking of lysosomal viscosity fluctuations induced by various chemotherapeutic agents, highlighting its significant potential as a powerful tool for early cancer diagnostics and fundamental lysosomal research.
    Keywords:  apoptosis; chemotherapy drug screen; ferroptosis; fluorescence imaging; lysosomal viscosity
    DOI:  https://doi.org/10.1002/smo2.70070
  23. Cell. 2026 Jul 24. pii: S0092-8674(26)00759-2. [Epub ahead of print]
    Dynamic dimer-of-dimers architecture defines Mg2+ transport in human CNNM4.
    Zhiyong Bai, X Edward Zhou, Wei Lü, Juan Du.
      Mg2+ is essential for all living organisms, yet its transport across mammalian membranes remains poorly understood. Here, we present cryoelectron microscopy (cryo-EM) structures of a full-length mammalian Mg2+ transporter on the plasma membrane, human CNNM4, in outward-facing and occluded states, revealing an unexpected tetrameric assembly organized as a dimer of asymmetric dimers-distinct from the symmetric dimers in prokaryotic homologs and long assumed for eukaryotic CNNMs. We show that Mg2+/ATP binding stabilizes the dynamic intracellular domains and promotes tetramerization, while an acidic patch binds additional Mg2+, potentially acting as a sensor to couple cytoplasmic Mg2+ levels to transport activity. Within the transmembrane domain, a key glutamate flips upon Na+ binding and destabilizes the Mg2+-binding site in the outward-facing state, thereby promoting Mg2+/Na+ exchange. Together, these findings establish a mechanistic framework for CNNM transport and regulation that diverges from prokaryotic models and links CNNM function to human physiology and disease.
    Keywords:  ATP binding; CNNM4; cryo-EM structure; dimer of asymmetric dimers; domain swapping; human; magnesium binding; magnesium homeostasis; magnesium sensing; magnesium transport
    DOI:  https://doi.org/10.1016/j.cell.2026.06.039
  24. Immunother Adv. 2026 ;6(1): ltag013
    Growth factor supportive care for chemotherapy-induced neutropenia suppresses antitumour immunity in checkpoint blockade-responsive pancreatic cancer.
    Brendan D Parent, Anthony E Kelly, Megan T Hoffman, Michael Dougan, Andrew J Aguirre, Stephanie K Dougan.
       Introduction: Growth factors, including granulocyte colony-stimulating factor (G-CSF; pegfilgrastim, filgrastim), are used for prophylaxis or treatment of chemotherapy-induced neutropenia, yet their effects on antitumour immunity remain incompletely understood. We previously found that serum from patients with pancreatic ductal adenocarcinoma (PDAC) treated with multiagent chemotherapy plus G-CSF drove differentiation of T cell-suppressive monocytes in vitro, suggesting that supportive care interventions may shape immune responses in this disease.
    Methods: We evaluated the immunologic and therapeutic impact of G-CSF in two murine PDAC models that differ in their baseline frequencies of infiltrating T cells and in their responsiveness to checkpoint blockade immunotherapy.
    Results: In poorly immunogenic, T-cell-low tumours, use of G-CSF did not affect tumour growth or response to chemo- or immunotherapy, although neutrophil recovery was improved in mice receiving FOLFIRINOX and G-CSF compared to chemotherapy alone. In immunogenic tumours with a robust endogenous T-cell response, combination anti-PD1 and anti-CTLA-4 therapy resulted in durable tumour clearance. Combination with G-CSF diminished the effectiveness of checkpoint blockade and resulted in significantly fewer cured mice.
    Conclusion: G-CSF, commonly used for supportive care with FOLFIRINOX and other chemotherapy regimens, induces systemic immune suppression that can reduce the efficacy of T-cell-targeting immunotherapies.
    Keywords:  G-CSF; checkpoint blockade; filgrastim; neutrophils; pancreatic cancer; pegfilgrastim
    DOI:  https://doi.org/10.1093/immadv/ltag013
  25. Nat Protoc. 2026 Jul 22.
    Identifying lipid-protein interactomes with functional lipid probes.
    Scotland E Farley, Gaelen Guzman, Berit Blume, Per Haberkant, Carsten Schultz, Fikadu G Tafesse.
      Cellular lipids shape health and disease through specific protein interactions, yet lipid-protein networks remain poorly defined. Despite rapid advances in functional lipid probes, the field still lacks a practical, dedicated protocol for conducting lipid-protein interaction studies. We describe detailed methods for determining lipid interactomes within cells using multifunctionalized lipid derivatives. We provide a protocol that details how to (i) treat cells with lipid derivatives and perform photochemistry to obtain lipid-protein conjugates, (ii) extract cellular lysates for downstream analysis, (iii) perform click chemistry on lysates with a fluorophore and observe lipid-protein conjugates by in-gel fluorescence and (iv) perform click chemistry on lysates with azide beads and prepare lipid-protein conjugates for proteomic analysis. We provide context on important parameters for each step and include guidelines for controls, as well as suggestions for troubleshooting based on common problems encountered during the preparation of this protocol. This protocol enables identification of proteins that bind to specific lipids across diverse biological systems and cellular states. The entire workflow from cell treatment to complete proteomic sample preparation requires ~15 h over 4 d, depending on the type of experimental readout (in-gel fluorescence or proteomics) and the usage of pause points. Practitioners are expected to be familiar with standard biochemical techniques, such as sterile sample handling and tissue culture and gel electrophoresis. Additional skills are needed for mass spectrometric analysis, and collaboration with a proteomics core facility is recommended. The described procedures uniquely enable the identification of the protein interactors (the interactome) of select lipid species, providing for a major advance in the characterization of the biological roles of lipids in cellular systems.
    DOI:  https://doi.org/10.1038/s41596-026-01405-2
  26. Free Radic Res. 2026 Jul 23. 1-11
    Novel antioxidant effects of deuterated polyunsaturated fatty acids against lipid peroxidation in cell membranes: hypothesis paper.
    Yoshiro Saito, Yeji Kim, Yasukazu Yoshida, Noriko Noguchi, Etsuo Niki.
      Lipid peroxidation (LPO) has long been implicated in the pathogenesis of various diseases and the role of antioxidants against LPO has been studied extensively. Recently, novel antioxidant functions of deuterated polyunsaturated fatty acids (D-PUFAs) in preventing LPO in the membranes and in humans have been reported by many research groups. The preventive and therapeutic potential of D-PUFAs against LPO and related diseases has received considerable attention, but the underlying molecular mechanisms and dynamics remain elusive. This hypothesis article summarizes state of the art preventive effects of D-PUFAs against LPO and cell damage reported in the literature and discusses the plausible mechanisms of action with an emphasis on the effects of membrane properties. Interestingly, it was found that cholesterol and oleic acid as well as D-PUFAs did not inhibit LPO in homogeneous solution, but they all suppressed LPO in the liposomal membranes, cell membranes, and partially in vivo. It is speculated that D-PUFAs suppress LPO in the membranes, at least in part, by physically obstructing the reaction between lipid peroxyl radicals and phospholipid substrates as well as by chemical and biochemical mechanisms. However, the proposed mechanism remains a hypothesis which should be validated directly in future experimental studies.
    Keywords:  Lipid peroxidation; antioxidant; cell membrane; deuterated fatty acid; free radicals
    DOI:  https://doi.org/10.1080/10715762.2026.2707391
  27. Cancer Res. 2026 Jul 21.
    Dual-MEK Inhibitor Atebimetinib Displays Broad Activity in RAS- and RAF-Mutant Tumors via Deep Cyclic Inhibition and Resisting RAF-Bypass.
    Sarah Kolitz, Anna Travesa, Amy Axel, Jason M Funt, Matthew S Nord, Amy Yamamura, Kevin D Fowler, Praveen Nair, Benjamin Zeskind, Brett M Hall, Peter King.
      Inappropriate activation of the mitogen-activated protein kinase (MAPK) pathway, often stemming from activating mutations in RAS or RAF, represents one of the most common oncogenic events in human cancer. However, currently approved RAS/RAF inhibitors target specific mutants that are only present in a small proportion of RAS- or RAF-activated tumors. Current MEK inhibitors (MEKi) are associated with class-effect toxicities and tumor escape via CRAF bypass of MEK blockade. To address these issues, we designed atebimetinib to resist CRAF-mediated bypass and enable a pharmacokinetic/pharmacodynamic (PK/PD) profile termed deep cyclic inhibition (DCI), an approach that transiently but deeply suppresses oncogenic signaling while allowing daily physiologic reset. Unlike chronic or intermittent approaches, DCI optimized depth and duration of MEK suppression on a daily cycle, blunting rebound signaling while preserving recovery windows for normal tissues. Functioning as an allosteric, selective MEKi, atebimetinib potently inhibited ERK phosphorylation in vitro and in vivo, resisted CRAF bypass, and was well tolerated and more efficacious in xenograft models of cancer compared with current MEK inhibitors. Overall, these findings establish atebimetinib as a dual-MEK inhibitor with the potential to provide mutation-agnostic inhibition of the MAPK pathway while leveraging DCI, designed to avoid toxicities associated with existing MEK inhibitors. Atebimetinib offers MEK inhibition that is durable and tolerable, supporting the potential of this therapeutic paradigm.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4907
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