bims-cagime 2026-08-30 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–08–30
28 papers selected by
Kıvanç Görgülü, Technical University of Munich

RevMed's RAS inhibitor gains landmark FDA approval for pancreatic cancer.
Single-Dose L-Lysine-Induced Pancreatitis Followed by Pancreatic Neoplastic Progression in Adult Kras/Trp53-Driven Mice.
Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer.
RASolute 302: Lessons Learned and the Road Ahead in Pancreatic Cancer.
Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling.
Membrane remodeling by the collective action of caveolin-1.
Ninjurin-1 mediates hepatic ischemia-reperfusion injury.
Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
Allele-Specific Mechanisms Guide Salvage Therapy to Overcome Daraxonrasib Resistance in Pancreatic Cancer.
Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer.
Differential regulation of the proliferative and autophagic responses in murine and human pancreatic cancer cells.
Virtual Cell Challenge 2026: Benchmarking zero-shot generalization across cellular contexts.
Precision immunotherapy in metastatic pancreatic cancer: OPTIMIZE-1 biomarker-driven patient stratification for future studies.
Partial fluidization theory of collective cell migration.
Endolysosomal remodeling and acidity dictates ferroptosis sensitivity to iron oxide nanoparticles.
Acquired Resistance to the PRMT5 Inhibitor Confers Collateral Sensitivity to MEK Inhibition in MTAP-Null Non-Small Cell Lung Cancer.
Micrometastasis as a distinct immunobiological state and therapeutic target.
A programmable lipid-triggered allosteric site modulates LC3 LIR receptor binding activity.
Regulation of Lipid Oxidation and Ferroptosis By a Tunable Axis of Vitamin E, High-Density Lipoprotein, and Scavenger Receptor Class B Type 1.
The long return on discovery science in cancer therapeutics.
Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
SpotMAX: A generalist framework for multidimensional automatic spot detection and quantification.
An evolutionary analysis of lysophospholipid acyltransferases generating membrane phospholipid diversity.
Stage-Specific Prognostic Impact of Longitudinal Body Composition Changes in Patients with Pancreatic Ductal Adenocarcinoma Treated with FOLFIRINOX: A Dual-Cohort Study.
The ongoing first-line treatment race for metastatic pancreatic ductal adenocarcinomas: will a tough disease lose its horror?
scProtoTransformer: Scalable reference mapping across molecules, cells, and donors.
A membrane insertion code for intrinsically disordered proteins.
Plotgardener App: a graphical interface for publication-ready genomic visualization.

Nat Rev Drug Discov. 2026 Aug 27.

RevMed's RAS inhibitor gains landmark FDA approval for pancreatic cancer.

Asher Mullard.

DOI: https://doi.org/10.1038/d41573-026-00145-y
Methods Protoc. 2026 Aug 10. pii: 116. [Epub ahead of print]9(4):

Single-Dose L-Lysine-Induced Pancreatitis Followed by Pancreatic Neoplastic Progression in Adult Kras/Trp53-Driven Mice.

Akihiro Kaneda, Masahiro Yoshida, Yoshiya Kawaguchi, Kenichiro Furuyama.

  Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, highlighting the need for reproducible experimental systems that model pancreatic injury and subsequent neoplastic progression. Adult-onset genetically engineered models in which oncogenic Kras and mutant Trp53 are induced in the pancreas provide a relevant platform for studying PDAC pathogenesis, but efficient neoplastic progression often requires concomitant pancreatic injury. Cerulein-induced pancreatitis is widely used to provide an injury-associated inflammatory stimulus that promotes PDAC progression; however, repeated-injection regimens are labor-intensive and increase cumulative handling stress in animals. Here, we describe a dose-optimized, single-dose L-Lysine protocol designed to induce acute pancreatitis and characterize subsequent pancreatic neoplastic progression in adult-onset Kras/Trp53-driven mice. Tamoxifen-treated Ptf1aCreER/+; KrasLSL-G12D/+; Trp53LSL-R172H/+; Rosa26-RFP mice received a single intraperitoneal injection of L-Lysine, followed by biochemical, histological, and immunohistochemical assessment of pancreatic injury and tumor development. A single 2.0 g/kg L-Lysine injection induced sublethal acute pancreatitis characterized by increased serum pancreatic enzymes, interstitial edema, inflammatory cell infiltration, acinar cell necrosis, and rapid mitochondrial alterations. During 3-6 months of follow-up, mice developed multifocal acinar-to-ductal metaplasia, PanIN lesions, invasive PDAC, and peritoneal dissemination. This protocol provides a simple, synchronized, and less labor-intensive model for studying pancreatic injury and subsequent neoplastic progression in adult-onset Kras/Trp53-driven mice.

Keywords:  L-lysine; adult-onset mouse model; pancreatic ductal adenocarcinoma; pancreatitis; protocol

DOI:  https://doi.org/10.3390/mps9040116
Nat Genet. 2026 Aug 26.

Developmental and MAPK-responsive transcription factors regulate distinct malignant cell states and associated genetic dependencies in pancreatic cancer.

Pasquale Laise, Mikko Turunen, Alvaro Curiel-Garcia, Lorenzo Tomassoni, H Carlo Maurer, Ela Elyada, Bernhard Schmierer, Jeremy Worley, Jordan Kesner, Xiangtian Tan, Ester Calvo Fernandez, Yuanqing Xue, Yining Chen, Kelly Wong, Urszula N Wasko, Somnath Tagore, Alexander L E Wang, Sabrina Ge, Alina C Iuga, Aaron T Griffin, Winston Wong, Gulam A Manji, Mariano J Alvarez, Faiyaz Notta, David A Tuveson, Kenneth P Olive, Andrea Califano.

There is broad consensus that the malignant epithelial cells of human pancreatic ductal adenocarcinoma (PDA) comprise multiple, molecularly distinct states. Yet precise characterization of how these are regulated-including their mechanistic determinants, dependencies, plasticity and functional properties-remains elusive. Single-cell master regulator (MR) analysis of multiple PDA cohorts identified malignant cells in three co-existing, molecularly distinct developmental lineage states, with distinct histopathological morphologies and spatial architecture. These include a poorly differentiated lineage driven by epithelial-mesenchymal-transition-related MRs and two well-differentiated states driven by gastrointestinal epithelial development and pancreatic development MRs, respectively. Furthermore, each state comprises two epigenetically distinct substates with low versus high MAPK signaling activity. Barcode-based lineage tracing confirmed both spontaneous and treatment-dependent cross-state plasticity. Furthermore, loss-of-function studies confirmed state-specific MR essentiality, while their ectopic expression effectively reprogrammed cell state, in vitro and in vivo, thus providing a mechanism-based foundation for PDA heterogeneity and a roadmap for pharmacological targeting.

DOI: https://doi.org/10.1038/s41588-026-02714-8
Oncologist. 2026 Aug 28. pii: oyag346. [Epub ahead of print]

RASolute 302: Lessons Learned and the Road Ahead in Pancreatic Cancer.

Andrew H Ko.



Keywords:  Pancreatic cancer; RAS inhibitor; clinical trial; daraxonrasib; dropout

DOI:  https://doi.org/10.1093/oncolo/oyag346
Sci Adv. 2026 Aug 28. 12(35): eaec4519

Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling.

Kohta Takahashi, Nario Tomishige, Mitsuhiro Abe, Gašper Šolinc, James Rae, Toshiyuki Yamaji, Frédéric Przybilla, Ludovic Richert, Nicolas Humbert, Takefumi Uemura, Thomas Wollert, Satoshi Waguri, Kentaro Hanada, Yasushi Sako, Gregor Anderluh, Robert G Parton, Yves Mély, Catherine Tomasetto, Fabien Alpy, Toshihide Kobayashi.

The physiological role of lipid asymmetry in intracellular membranes remains poorly understood. Here, we show that sphingomyelin (SM), typically confined to the lumen of the trans-Golgi network (TGN), is exposed on its cytoplasmic surface by the action of the Golgi-associated protein, Golgi-associated gamma-adaptin ear-containing adenosine 5'-diphosphate-ribosylation factor-binding protein 1 (GGA1). This exposure is driven by the GGA1 GAT domain, which induces lipid scrambling in a manner dependent on membrane curvature and cholesterol. SM exposure coincides with the exit of mannose 6-phosphate receptors from the TGN, a process essential for lysosomal enzyme trafficking. Furthermore, SM is transferred to autophagic membranes, where it facilitates autophagosome-lysosome fusion. These findings reveal a previously unrecognized role for lipid remodeling in membrane trafficking and autophagy.

DOI: https://doi.org/10.1126/sciadv.aec4519
Nat Commun. 2026 Jul 22. pii: 8949. [Epub ahead of print]17(1):

Membrane remodeling by the collective action of caveolin-1.

Korbinian Liebl, Gregory A Voth.

Caveolin-1 proteins scaffold 50-100 nm large invaginations in the plasma membrane to mediate critical cellular processes. As revealed recently by cryo-electron microscopy, several caveolin-1 protomers can fold into a disk-like structure that embeds in the cytoplasmic leaflet. This 8S complex represents a basal component to drive membrane curvature via higher-order interactions. The biophysical mechanisms behind the membrane remodeling, however, are elusive. To address this shortcoming, we develop a bottom-up coarse-grained model to overcome the substantial computational limitations for this large system. During simulations with the coarse-grained model, the complexes increasingly coordinate as partially mediated by attractive electrostatic interactions between scaffolding domains. The coordination of complexes strongly correlates with membrane protrusion, as approaching complexes amplify localized stress in the exoplasmic leaflet. Thus, proximity of two CAV1-8S complexes induces dynamic curvature generation that can facilitate access for signaling partners. This mechanism is further explored through simulations of clusters of multiple CAV1-8S complexes that form large-scale membrane invaginations, suggesting that caveolin-mediated membrane remodeling arises collectively from the coordinated action of multiple complexes rather than from isolated complexes.

DOI: https://doi.org/10.1038/s41467-026-75821-z
Sci Adv. 2026 Aug 28. 12(35): eaeg9496

Ninjurin-1 mediates hepatic ischemia-reperfusion injury.

Jan Mossemann, Brunna X Martins, Yixuan Zhao, Fiorelle Aguilar, Daria Taskina, Claire J Hur, Diana Nakib, Allen Volchuk, Gang Ye, Danish M Ali, Ali Mirzaesmaeili, Iram Siddiqui, Ghazal Goodarzi, Philip J Bilan, Irma B Stowe, Nobuhiko Kayagaki, Sonya MacParland, Spencer A Freeman, Neil M Goldenberg, Benjamin E Steinberg, Blayne A Sayed.

Lytic cell death pathways drive hepatic ischemia-reperfusion injury (IRI). The transmembrane protein ninjurin-1 (NINJ1) aggregates in the plasma membrane to permeabilize the cell during multiple cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1 mediates liver IRI and that its inhibition would mitigate injury. We found that NINJ1 is highly expressed in human liver tissue and that its up-regulation and activation correlate with early allograft dysfunction in liver transplant patients. Using a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. We therefore position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for liver transplantation.

DOI: https://doi.org/10.1126/sciadv.aeg9496
Cell Metab. 2026 Aug 28. pii: S1550-4131(26)00328-1. [Epub ahead of print]

Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.

Yong Tang, Ziqing Chen, Hirak Sarkar, Yong Wei, Sereno L Lopez-Darwin, Asael Roichman, Ji Woo Park, Qinglan Li, Cao Fang, Zihong Chen, James Gow, Minhong Shen, Jennifer Shi, Lifei Jiang, Richard Klar, Xiang Hang, Janette R Lugo, Christina J DeCoste, Jennifer M Miller, Wei Wang, Peter Romanienko, Alana L Welm, Ileana M Cristea, Liling Wan, Joshua D Rabinowitz, Yibin Kang.

  Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.

Keywords:  CD8(+) T cells; EVP; MTDH; PPARα; extracellular vesicles and particles; immunotherapy; lipid metabolism; tumor-liver interaction

DOI:  https://doi.org/10.1016/j.cmet.2026.08.003
Cancer Res. 2026 Aug 27.

Allele-Specific Mechanisms Guide Salvage Therapy to Overcome Daraxonrasib Resistance in Pancreatic Cancer.

Daniel Dorbin, Juliannie Herrera, Raven Davidson, Naveen Kumar Chandrashekar, Gabrielle Scheuber, Priyanga Jayakrishnan, Christabelle Rajesh, Grayson Johnson, Jason Yuan, Matthew A Sochor, John F Langenheim, Mohammed Aldakkak, Charles Messerly, Jacquelyn Wittmann, Aniko Szabo, Forough Azam Sayahpour, Nathan L Atallah, Francis C Peterson, Brian F Volkman, Mahmoud Ali, Eugene Ke, Douglas B Evans, Susan Tsai, Nikki K Lytle, Y David Seo, Razelle Kurzrock, G Aaron Hobbs, Mandana Kamgar, Thomas McFall.

Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly (~20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib resistant KRASG12R PDAC cells utilized EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to EGFR/RASWT dependence conferred sensitivity to trametinib. As clinical confirmation, a KRASG12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived tumoroid modeling predicted sensitivity to trametinib-based combination therapy. Despite the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control, and this patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-1181
Nat Commun. 2026 07 27. pii: 9105. [Epub ahead of print]17(1):

Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer.

Krishnan K Mahadevan, Ana S Maldonado, Bingrui Li, Aaron A Bickert, Adrian Kacperczyk-Perdyan, Shreyasee V Kumbhar, Sujan Piya, Amari M Sockwell, Sami J Morse, Kent Arian, Hikaru Sugimoto, Shabnam Shalapour, David S Hong, Timothy P Heffernan, Anirban Maitra, Raghu Kalluri.

Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.

DOI: https://doi.org/10.1038/s41467-026-75960-3
Autophagy Rep. 2026 ;5(1): 2715823

Differential regulation of the proliferative and autophagic responses in murine and human pancreatic cancer cells.

Ruohong Wang, Albert Sw Sohn, Jiangwei Li, Mohamad Assi.

  Pancreatic ductal adenocarcinoma (PDAC) cells rely on autophagy to adapt to microenvironmental stress. In our recent work, we showed that baseline autophagy flux levels shape the proliferative capacity of human PDAC cells. Here, we extend these findings by demonstrating that low baseline autophagy is consistently associated with enhanced proliferation in vitro and in vivo across multiple human and murine PDAC models. While this inverse relationship between autophagy flux and proliferation is conserved across species, the underlying regulatory mechanisms diverge. Namely, changes in baseline autophagy levels relied predominantly on canonical nutrient-sensing pathways in murine but not human PDAC cells. Additionally, we found that autophagy flux was regulated independently of the cell cycle or the genetic status of p53 (i.e., allelic deletion, point mutation). Collectively, our results reveal conserved phenotypic outcomes but divergent mechanisms, underscoring the need for parallel comparative approaches before extrapolating findings from mouse PDAC models to human disease.

Keywords:  Autophagy; cancer; cell signaling; cross-species; proliferation

DOI:  https://doi.org/10.1080/27694127.2026.2715823
Cell. 2026 Aug 26. pii: S0092-8674(26)00931-1. [Epub ahead of print]

Virtual Cell Challenge 2026: Benchmarking zero-shot generalization across cellular contexts.

Arc Virtual Cell Initiative Team

The Virtual Cell Challenge returns in 2026 with a more demanding test of biological generalization: zero-shot prediction across multiple independent cellular contexts. Participants will build models to predict gene knockdown responses in a new Arc-generated dataset comprising unseen cell lines. The goal is to determine whether the best models can meaningfully close the gap between preclinical experimental predictions and human biology.

DOI: https://doi.org/10.1016/j.cell.2026.08.004
Ann Pancreat Cancer. 2026 Aug 30. pii: 21. [Epub ahead of print]9

Precision immunotherapy in metastatic pancreatic cancer: OPTIMIZE-1 biomarker-driven patient stratification for future studies.

Ahmed Abdelhakeem, Hani M Babiker.



Keywords:  CD40 agonist; biomarkers; immunotherapy; mitazalimab; pancreatic cancer

DOI:  https://doi.org/10.21037/apc-26-0014
Commun Phys. 2026 ;9(1): 281

Partial fluidization theory of collective cell migration.

Igor S Aranson, Lev S Tsimring.

  Collective cell and tissue migration is crucial for various biological processes, including morphogenesis, wound healing, and cancer metastasis. Migrating cell monolayers often exhibit complex viscoelastic responses and coexistence of solid and liquid-like behaviors that are not well understood in the framework of existing theories. Here, we introduce a partial fluidization approach for collective cell migration. We treat the cell monolayer as a single albeit spatially and temporally non-uniform phase bridging two distinct states: a viscous liquid and a soft solid with an elastic response to shear. The continuous transition between these states is controlled by the fluidization order parameter that, in turn, depends on the normalized shear stress. The model successfully captures key experimental observations: solid-like plug flow of cells in a microfluidic channel, spatial coexistence of moving and immobile domains in cell monolayers, and solid body-like rotational flow of cells in a circular chamber. The approach provides insights into the physical mechanisms of cell migration. It can be extended to more realistic situations, such as confluent monolayers on curved, compliant, or degradable surfaces as well as three-dimensional proliferating tissues and chemical signaling.

Keywords:  Cellular motility; Fluids

DOI:  https://doi.org/10.1038/s42005-026-02702-8
Biomed Pharmacother. 2026 Aug 25. pii: S0753-3322(26)00911-X. [Epub ahead of print]203 119875

Endolysosomal remodeling and acidity dictates ferroptosis sensitivity to iron oxide nanoparticles.

Neus Daviu, Alberto Irigaray-Moreno, Carla Graciano-Casero, Domingo F Barber.

  Iron oxide nanoparticles (IONPs) exhibit remarkable anti-tumoral activity, largely mediated by the generation of reactive oxygen species (ROS). Although certain IONPs can induce ferroptosis, the determinants underlying cell-type-specific sensitivity remain poorly understood. Here, we provide novel mechanistic insight by demonstrating that lysosomal acidity and plasticity critically regulate iron mobilization, ROS compartmentalization, and the ferroptotic response triggered by dimercaptosuccinic acid-coated IONPs (DMSA‑IONPs) in MDA‑MB‑231 breast cancer and U87MG glioma cells. DMSA-IONPs generate ROS in both cell models, however, their subcellular localization markedly differed. In MDA-MB-231 cells, highly acidic lysosomes retained redox-active iron (Fe2+), leading to localized ROS accumulation, lysosomal enlargement and pronounced lipid peroxidation, ultimately inducing ferroptosis, which was reverted by the anti-ferroptosis drug Ferrostatin-1. In contrast, the less acidic lysosomes of U87MG cells released iron into the cytosol and mitochondria, resulting in diffuse ROS production without lipid peroxidation and conferring resistance to ferroptosis despite higher nanoparticle uptake. While IONP‑mediated ROS generation via iron mobilization and Fenton‑like reactions is well established, our findings identify lysosomes as critical determinants of cellular responses to IONPs exposure. Specifically, lysosomal acidity and endolysosomal trafficking govern ferroptotic sensitivity to IONPs by controlling the site of ROS accumulation. Our results demonstrate that IONP-induced ferroptosis depends not only on total ROS levels but also on ROS subcellular distribution, with ROS accumulated in lysosomes triggering lipid peroxidation of these organelles. These insights highlight the importance of evaluating lysosomal physiology across tumor type to optimize nanoparticle-based ferroptosis therapies, particularly for tumors resistant to apoptosis.

Keywords:  Cancer cell death; Ferroptosis; Lipid peroxidation; Lysosomal damage; Lysosome-dependent cell death; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biopha.2026.119875
Biomolecules. 2026 Aug 17. pii: 1198. [Epub ahead of print]16(8):

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 methylthioadenosine (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 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 accompanied by cross-resistance to mechanistically distinct PRMT5 inhibitors. Notably, this phenotype was not fully explained by altered PRMT5 activity or changes in MTA levels. High-throughput drug screening of paired sensitive and resistant cells revealed increased sensitivity to MEK inhibitors following acquisition of MRTX1719 resistance in KRAS-wildtype NSCLC cells. Consistently, resistant cells exhibited rewired MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as a reproducible collateral vulnerability associated with acquired MRTX1719 resistance in MTAP-null NSCLC models and support further evaluation of MEK inhibition as a potential treatment-switching strategy following resistance.

Keywords:  MAPK signaling; MEK inhibition; MTA-cooperative PRMT5 inhibitor; MTAP-null; PRMT5; acquired resistance

DOI:  https://doi.org/10.3390/biom16081198
Trends Immunol. 2026 Aug 28. pii: S1471-4906(26)00189-4. [Epub ahead of print]

Micrometastasis as a distinct immunobiological state and therapeutic target.

Silvia Avalle, Toni Celià-Terrassa.

  Metastasis is an inefficient cellular process in which most disseminated tumor cells fail to form secondary lesions in distant tissues due to hostile conditions, such as protective immune surveillance. The few cells that survive these threats can seed subclinical metastatic lesions, known as micrometastases, which are the least-known stage of the metastatic cascade. In this study, we review micrometastasis immunobiology, which differs from that of larger, clinically manifested metastasis. Key mechanisms such as epithelial-to-mesenchymal transition, stemness, dormancy, and immune evasion shape this bottleneck of metastasis, determining long-term disease evolution, therapy responses, and patient outcomes. Understanding micrometastasis immunology may reveal therapeutic opportunities to fully eradicate disseminated cells. Thus, we discuss emerging time-tailored immunopreventive strategies to intercept the progression to overt metastasis.

Keywords:  MRD; immune evasion; immunoediting; immunotherapy; metastasis; micrometastasis

DOI:  https://doi.org/10.1016/j.it.2026.07.010
Nat Commun. 2026 Aug 28. pii: 9144. [Epub ahead of print]17(1):

A programmable lipid-triggered allosteric site modulates LC3 LIR receptor binding activity.

Deepanshi Gahlot, Jesu Castin, Shruti Mathur, Debajyoti Das, Ajit Kumar, Akanksha Arun, Chandrima Gain, Mridul Sharma, Ravi Kant Pal, Niyati Jain, Bichitra K Biswal, Rajat Singh, Lipi Thukral.

Membrane recruitment is a fundamental regulator of protein function. However, the allosteric mechanisms by which lipid binding controls protein activity remain poorly understood. In autophagy, the ubiquitin-like protein LC3 is lipid-anchored to autophagosomes, where it is essential for receptor recruitment and vesicle formation. While LC3-receptor interactions are structurally well defined, how membrane engagement governs LC3 functional dynamics has remained enigmatic. Here, we uncover that membrane binding triggers a major conformational transition in LC3, exposing functional pockets that are occluded in its cytosolic form. We demonstrate that this shift is mediated by dynamic coupling between the allosteric site (α3-loop5-β3-loop6) and the functional binding pockets. To conclusively test this mechanism, we utilised an ensemble-based protein design strategy guided by molecular dynamics to engineer the allosteric site. From a series of mutants, two variants emerged that stabilized LC3 conformation in either active or inactive state on the membrane. X-ray crystal structures of mutant LC3, biophysical assays, super-resolution microscopy, and TEM confirmed that the activated allosteric site mutant facilitates receptor binding and cargo capture. In contrast, the inactive variant is functionally inert on the membrane. Our work identifies a fundamental lipid-triggered allosteric site in LC3 that is critical for autophagy regulation and broader implications of membrane-dependent reprogrammable protein activities.

DOI: https://doi.org/10.1038/s41467-026-76697-9
J Biol Chem. 2026 Aug 27. pii: S0021-9258(26)02369-0. [Epub ahead of print] 113497

Regulation of Lipid Oxidation and Ferroptosis By a Tunable Axis of Vitamin E, High-Density Lipoprotein, and Scavenger Receptor Class B Type 1.

Jonathan S Rink, Andrea E Calvert, Sophia M Lamperis, Alexandra Moxley, Adam Yuh Lin, SonBinh T Nguyen, Leo I Gordon, C Shad Thaxton.

  Ferroptosis is caused by lethal peroxidative damage to cell membrane phospholipids (PL) containing polyunsaturated fatty acid (PUFA) tail groups. Mechanisms to control cell membrane PL oxidation and ferroptosis include cellular expression of glutathione peroxidase 4 (GPx4), which repairs oxidized cell membrane PL, and the lipophilic antioxidant alpha-tocopherol (α-toc), an active form of Vitamin E. Data show that α-toc can rescue cells from ferroptosis in vitro and in vivo even in the absence of GPx4. Yet, pathways by which α-toc is transported in blood, for instance in high- and low-density lipoproteins (HDL and LDL), for delivery to target cells to prevent PL oxidation and ferroptosis are unknown. We hypothesized that HDLs specifically target delivery of α-toc to the cell membrane to regulate PL oxidation and sensitivity to ferroptosis. We employed native lipoproteins and synthetic HDL-like nanoparticles made using either organic or gold nanoparticle cores (ocHDL NP or Au-HDL NP, respectively). The bottom-up synthesis strategies enabled control over the physicochemical properties of HDL NP, including α-toc content. Using cancer and neuronal cell models, our data show native HDLs and synthetic HDL NPs deliver α-toc by binding cell membrane receptor scavenger receptor class B type 1 (SR-B1) to prevent PL oxidation and ferroptosis. Additionally, data show Au-HDL NP, previously shown to bind SR-B1, reduce GPx4, and induce ferroptosis can rescue cells from ferroptosis when synthesized to contain α-toc. Overall, our data demonstrate a tunable cellular redox axis whereby HDLs containing α-toc target SR-B1 to regulate sensitivity to ferroptosis.

Keywords:  SR-B1; ferroptosis; high-density lipoproteins; oxidation; α-tocopherol

DOI:  https://doi.org/10.1016/j.jbc.2026.113497
Nat Rev Cancer. 2026 Aug 28.

The long return on discovery science in cancer therapeutics.

Cian Murphy, Samuel Hume, Charles Swanton.

DOI: https://doi.org/10.1038/s41568-026-00978-0
Dev Cell. 2026 Aug 28. pii: S1534-5807(26)00290-X. [Epub ahead of print]

Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.

Matej Durik, Mona Karout, Daniel Sampaio Gonçalves, Tania Knauer-Meyer, Coralie Spiegelhalter, Nadia Messaddeq, Marco Seehawer, Pauline Stephan, Dmitry V Bulavin, Yann Herault, Lars Zender, William M Keyes.

  Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here, we identify that senescent cells dispose of large fragments through cell-to-cell adhesion, which we term "senescent-cell adhesion fragments" (SCAFs). Found in many senescent states, including human and mouse cells, and mouse tissues, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreases SCAF formation but induces senescent-cell death, due to an inability to shed damaged mitochondria. Live imaging and proteomics show that SCAFs ultimately rupture, releasing a complex proteome, including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Immunostaining also reveals amyloid-like material in senescent cells that can be externalized through fragmentation. Altogether, these findings identify a feature that facilitates senescent cell survival but also externally deposits damaged intracellular contents, with implications for cancer and neurodegeneration.

Keywords:  DAMPs; aging; amyloid; cancer; cell-cell adhesion; debris; mitochondria; senescence

DOI:  https://doi.org/10.1016/j.devcel.2026.08.002
Sci Adv. 2026 Aug 28. 12(35): eadw3811

SpotMAX: A generalist framework for multidimensional automatic spot detection and quantification.

Francesco Padovani, Ivana Čavka, Ana Rita Rodrigues Neves, Cristina Piñeiro López, Nada Al-Refaie, Leonardo Bolcato, Dimitra Chatzitheodoridou, Yagya Chadha, Pablo Lagos, Timon Stegmaier, Xiaofeng A Su, Jette Lengefeld, Daphne S Cabianca, Simone Köhler, Kurt M Schmoller.

The analysis of spot-like structures is a widespread task in microscopy image analysis. Existing solutions are typically specific to single applications and do not use multidimensional information, often leaving manual annotation as the only option. Here, we present SpotMAX, a generalist AI-assisted framework for automated spot detection and quantification. SpotMAX detects spots in three-dimensional (3D) data and leverages the full scope of multidimensional datasets with an easy-to-use graphical user interface and a framework for cell segmentation and tracking. Tested on a large 3D dataset, SpotMAX outperforms or is on par with state-of-the-art tools and expert human annotators. We applied SpotMAX across diverse experimental questions, ranging from meiotic crossover events in Caenorhabditis elegans to mitochondrial DNA dynamics in Saccharomyces cerevisiae and telomere length in mouse stem cells, leading to new biological insights. With its flexibility in integrating other AI models into a holistic analysis workflow, we anticipate that SpotMAX will become the standard for spot analysis in microscopy data.

DOI: https://doi.org/10.1126/sciadv.adw3811
Front Immunol. 2026 ;17 1838657

An evolutionary analysis of lysophospholipid acyltransferases generating membrane phospholipid diversity.

Hideo Shindou, Yosuke Kawai.

  All living organisms are enclosed by biological membranes composed primarily of phospholipids. The diversification of membrane lipids has shaped key membrane functions, including signaling, membrane protein regulation, and immune responses, and may also have driven organismal evolution. In humans, this diversity is mainly generated by lysophospholipid acyltransferases (LPLATs), yet the evolutionary distribution and diversity of LPLATs across organisms remain poorly understood, particularly in pathogens. Here, we systematically identified candidate LPLAT proteins belonging to two major families in representative prokaryotic and eukaryotic species and reconstructed their phylogenetic relationships. The analysis reveals a marked expansion and diversification of LPLATs in vertebrates and suggests the possibility of pathogen-specific LPLAT expansions. These findings suggest that the diversification of membrane phospholipid remodeling enzymes may accompany increasing biological complexity and pathogenicity. This study provides an evolutionary framework for understanding phospholipid metabolism and highlights pathogen LPLATs as potential targets for exploring host defense mechanisms.

Keywords:  LPLAT; cellular membrane; membrane diversity; membrane remodeling; pathogen; phospholipid

DOI:  https://doi.org/10.3389/fimmu.2026.1838657
J Clin Med. 2026 Aug 13. pii: 6282. [Epub ahead of print]15(16):

Stage-Specific Prognostic Impact of Longitudinal Body Composition Changes in Patients with Pancreatic Ductal Adenocarcinoma Treated with FOLFIRINOX: A Dual-Cohort Study.

Ahmet Demirel, Bora İnceöz, Ali Kaan Güren, Burak Paçacı, Erkam Kocaaslan, Mustafa Alperen Tunç, Fırat Akagündüz, Emek Kaya, Canan Çimşit, Nazım Can Demircan, İbrahim Vedat Bayoğlu.

  Background: Computed tomography (CT)-derived body composition has emerged as a promising prognostic biomarker in pancreatic ductal adenocarcinoma (PDAC). However, most previous studies have relied on baseline measurements and evaluated either resected or metastatic disease separately. We aimed to investigate the prognostic significance of both baseline and longitudinal CT-derived body composition changes in clinically distinct but therapeutically homogeneous cohorts of patients with PDAC receiving FOLFIRINOX. Methods: This retrospective single-center study included 98 consecutive patients with histologically confirmed PDAC treated with FOLFIRINOX between 2018 and 2025. Forty-seven patients underwent curative-intent resection followed by adjuvant modified FOLFIRINOX, whereas 51 patients with unresectable metastatic disease received first-line FOLFIRINOX. Skeletal muscle index (SMI) and visceral adipose tissue (VAT) were quantified on serial CT scans obtained at the third lumbar vertebral level before treatment and during therapy. Follow-up CT scans suitable for longitudinal body composition analysis were available for 46 of 51 patients (90.2%) in the metastatic cohort. Overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: Baseline CT-derived body composition parameters were not independently associated with survival in either cohort. In the resected cohort, preservation of visceral adiposity during treatment (follow-up VAT > 100 cm2) independently predicted improved OS in a multivariable model including three covariates (HR 0.460, 95% CI 0.220-0.960; p = 0.039). Median DFS and OS were 11.7 months (95% CI 6.5-16.9) and 20.9 months (95% CI 12.1-29.7), respectively. In the metastatic cohort, treatment-related skeletal muscle loss (ΔSMI) independently predicted inferior OS in a multivariable model including four covariates (HR 0.949, 95% CI 0.913-0.986; p = 0.008), while lung metastasis was also independently associated with worse survival (HR 5.792, 95% CI 1.880-17.841; p = 0.002). Median PFS and OS were 9.7 months (95% CI 8.0-11.4) and 12.7 months (95% CI 9.9-15.5), respectively. Conclusions: Longitudinal CT-derived body composition changes may provide additional prognostic information beyond baseline measurements in patients with PDAC receiving FOLFIRINOX. Preservation of visceral adiposity was associated with improved survival following curative-intent resection, whereas greater treatment-related skeletal muscle loss was associated with poorer survival in metastatic disease. These findings suggest that the prognostic relevance of body composition may vary according to disease stage and should be considered hypothesis-generating pending validation in larger prospective multicenter studies.

Keywords:  FOLFIRINOX; body composition; cachexia; computed tomography; pancreatic ductal adenocarcinoma; prognosis; sarcopenia; skeletal muscle index; visceral adipose tissue

DOI:  https://doi.org/10.3390/jcm15166282
Future Oncol. 2026 Aug 28. 1-9

The ongoing first-line treatment race for metastatic pancreatic ductal adenocarcinomas: will a tough disease lose its horror?

Wolfram C M Dempke, Christoph Sippel, Klaus Fenchel, Volker Heinemann, Eric van Cutsem, Dirk Arnold.

  Pancreatic ductal adenocarcinomas (PDACs) are found to account for more than 5% of all cancer-related deaths worldwide. The 5-year survival rates are still low (<5% for in the metastatic setting). In patients with metastatic disease, combination chemotherapy regimens are currently standard of care. PDACs are K-RAS addicted (incidence >90%), however, RAS oncogenes have been regarded to be "undruggable." Several highly specific inhibitors have been developed with atebimetinib (MEK inhibitor), daraxonrasib (tri-complex pan-K-RAS inhibitor), zoldonrasib (tri-complex K-RAS G12D inhibitor), INCB161734 (non-covalent ON/OFF inhibitor specific for K-RAS G12D), HRS-4642 (liposomal G12D inhibitor), and setidegrasib (G12D degrader) currently undergoing phase III evaluation in first-line PDACs. Five trials (RASolute-305 [zoldonrasib], DAWN-303 [INCB161734], MAPKeeper-301 [atebimetinib]), HRS-4642, and setidegrasib are comparing chemotherapy plus inhibitor with chemotherapy alone. In contrast, RASolute-303 (daraxonrasib) is a three-arms randomized trial with an additional arm being daraxonrasib monotherapy. Since the benefits provided by chemotherapy regimens are limited, it is conceivable that the novel targeted approaches may have the potential to overcome these limitations. Of note, outcomes for some of these compounds numerically exceeded the historical benchmarks with standard chemotherapy suggesting that a chemotherapy backbone might no longer be needed in the future.

Keywords:  K-RAS and MEK inhibitors; Metastatic pancreatic ductal adenocarcinomas; first-line therapy; palliative chemotherapy; phase III trials

DOI:  https://doi.org/10.1080/14796694.2026.2725499
Sci Adv. 2026 Aug 28. 12(35): eaef0286

scProtoTransformer: Scalable reference mapping across molecules, cells, and donors.

Zhenchao Tang, Haohuai He, Shouzhi Chen, Jun Zhu, Tianxu Lv, Jiale Zhou, Jiehui Huang, Yaokun Li, Guanxing Chen, Linlin You, Calvin Yu-Chian Chen.

The rapid accumulation of single-cell data has made it possible to comprehensively characterize biological systems at molecular, cellular, and donor levels. However, scalable reference mapping across different resolutions remains a major challenge in current research. Here, we propose scProtoTransformer, a prototype-based Transformer architecture designed to achieve scalable reference mapping across molecular, cell, and donor levels. scProtoTransformer introduces a knowledge-guided prototype tokenizer that projects gene expression into biologically interpretable pathway prototypes, effectively reducing numerical batch effects while preserving biological semantic patterns. Furthermore, by leveraging knowledge distilled from the foundation model and a dynamic supervised fine-tuning strategy, scProtoTransformer achieves robust biological representations with reduced pretraining requirements. Benchmark experiments across molecular, cell, and donor-level reference mapping demonstrate that scProtoTransformer delivers competitive or even superior performance compared with state-of-the-art approaches while providing interpretability through biological prototypes. Together, these results establish scProtoTransformer as a unified framework for scalable reference mapping, laying the foundation for systematic understanding from genes to individuals.

DOI: https://doi.org/10.1126/sciadv.aef0286
Elife. 2026 Aug 26. pii: RP111515. [Epub ahead of print]15

A membrane insertion code for intrinsically disordered proteins.

Fidha Nazreen Kunnath Muhammedkutty, Huan-Xiang Zhou.

  Membrane association of intrinsically disordered proteins (IDPs) mediates various cellular functions including membrane remodeling and signal transduction. Whereas membrane association through amphipathic helices and polybasic motifs is well understood, sequence determinants for the insertion of aromatic residues into the membrane hydrophobic core are still poorly characterized. Here, we decipher the sequence code for membrane insertion of aromatic-centered motifs. For an initial set of ten 9-residue aromatic-centered sequences, all-atom molecular dynamics simulations and the positioning of proteins in membranes (PPM) method produced very similar membrane insertion propensities. Applying PPM to a full library of 1.2×106 sequences with an F, W, or Y residue flanked by L, R, G, N, or E at four positions on either side, we found that aliphatic (L) and basic (R) residues favor membrane insertion, whereas acidic (E) and polar (N) residues disfavor it. Guided by these rules, we developed a mathematical model dubbed AroMIP (Aromatic Membrane Insertion Predictor) to predict the membrane insertion propensities of aromatic-centered motifs. AroMIP achieves 91.2, 92.0, and 99.7% accuracies for F-, W-, and Y-centered motifs, respectively, in disordered regions of the human proteome and is available as a web server at https://zhougroup-uic.github.io/AroMIP/. The present work provides the sequence basis and a mechanistic understanding of how IDPs employ aromatic-centered motifs to drive membrane insertion, and enriches the tools for the study of IDP-membrane association.

Keywords:  aromatic residues; cell membranes; human; intrinsically disordered regions; membrane insertion; molecular biophysics; structural biology

DOI:  https://doi.org/10.7554/eLife.111515
Bioinformatics. 2026 Aug 28. pii: btag649. [Epub ahead of print]

Plotgardener App: a graphical interface for publication-ready genomic visualization.

Rishabh Sharma Vemuri, Abiye Berhanu, Grace E Kenney, Sarah M Parker, Jeffrey T Phillips, J P Flores, Tooba Rashid, Douglas H Phanstiel.

SUMMARY: Plotgardener is an R package used for generating high-quality genomic visualizations. Despite its broad range of functions and versatility, its reliance on code presents a barrier for many potential users. To address this, we developed a macOS desktop application version of Plotgardener that enables users to create publication-ready genomic plots with no programming experience. The application employs a modular architecture comprising an Electron.js backend, a React frontend, and a Python parser that dynamically analyzes the Plotgardener package to ensure interface fields remain synchronized with package updates. By lowering the technical barrier to advanced genomic visualization, the Plotgardener desktop application broadens access to powerful visualization workflows for researchers and clinicians.
AVAILABILITY: The current release of the Plotgardener App is an open source macOS desktop application built with Electron (Node.js), featuring a React frontend and a Python-based parser. The download link is available at https://phanstiellab.github.io/plotgardener/articles/guides/plotgardenerApp.html and on Zenodo (doi: https://doi.org/10.5281/zenodo.21684228). The source code is hosted on GitHub at https://github.com/rishabhsvemuri/ThePlotgardenerApp.
SUPPLEMENTARY INFORMATION: The original R package documentation can be found at https://phanstiellab.github.io/plotgardener/.

DOI: https://doi.org/10.1093/bioinformatics/btag649