bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–03–29
29 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states.
  2. Copper deprivation reprograms antioxidant defense to suppress ferroptosis via SLC7A11.
  3. Dissecting histological transformation.
  4. PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis.
  5. Membrane Curvature Activates Src kinase and Promotes Metastatic Cancer Cell Survival.
  6. SenCat: Cataloging human cell senescence through multiomic profiling of multiple senescent primary cell types.
  7. Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
  8. Local gene editing of fibroblasts in tumors reveals a new cancer-associated fibroblast state.
  9. Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: the phase 2 POLAR trial.
  10. Repair condensates and lipid domains in lysosome integrity.
  11. Spatially-resolved subtype progression reveals metabolic vulnerabilities in pancreatic ductal adenocarcinoma.
  12. Real-time measurement of the ATG8 lipidation reaction by fluorescence spectroscopy.
  13. Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer.
  14. Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer.
  15. Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade.
  16. Single-Cell RNA-Sequencing Reveals Cachectic Satellite Cell Population in Muscle of Male Mice With Cancer Cachexia.
  17. Redox cycling nitroxide limits cellular iron availability and selectively inhibits iron-sulfur cluster metabolism.
  18. The role of NINJ1 in diseases.
  19. Interplay between membrane protrusive activities and their adhesion strength regulates cell migration.
  20. Senescent cancer-associated fibroblasts drive early-stage lymph node metastasis in pancreatic cancer through lactate-mediated metabolic-epigenetic rewiring.
  21. Chart builder: an interactive tool for user driven data visualization in the electron microscopy data bank.
  22. Novel L1CAM-antibody drug conjugates exert potent anti-tumor activity in preclinical models of even advanced pancreatic cancer.
  23. Tmn blocks phage spread via plasmolysis and triggers synergistic defence responses.
  24. Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions.
  25. Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
  26. Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.
  27. The cytoplasm of living cells can sustain transient and steady intracellular pressure gradients.
  28. Establishment of Gemcitabine-resistant Mouse Pancreatic Ductal Adenocarcinoma Cell Line and Possible Therapeutic Agents.
  29. Biophysical trade-offs in antibody evolution are resolved by conformation-mediated epistasis.
  1. Dev Cell. 2026 Mar 23. pii: S1534-5807(26)00082-1. [Epub ahead of print]
    Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states.
    Stefan R Torborg, Jung Yun Kim, Anupriya Singhal, Olivera Grbovic-Huezo, Matilda Holm, Katherine Wu, Xuexiang Han, Yu-Jui Ho, Caj Haglund, Michael J Mitchell, Scott W Lowe, Lukas E Dow, Kenneth L Pitter, Francisco J Sanchez-Rivera, Andre Levchenko, Tuomas Tammela.
      Control of cell identity and number is central to tissue function, yet principles governing the organization of malignant cells remain poorly understood. Using genetically engineered mouse models and orthotopic allografts with dual WNT reporter systems, we discover that pancreatic ductal adenocarcinoma (PDAC) organizes in a stereotypical pattern, whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Lineage tracing reveals that the WNT-R state is transient and gives rise to a stable WNT-S state. A subset of WNT-S cells expressing DLL1 forms a functional niche for WNT-R cells. The genetic inactivation of WNT secretion or Notch pathway components, or the cytoablation of WNT-S cells, disrupts PDAC tissue organization, suppressing tumor growth and metastasis. Analysis of human PDAC tissues confirms conservation of these populations. PDAC growth depends on an intricately controlled equilibrium of functionally distinct cancer cell states, revealing the fundamental principles governing solid tumor organization and therapeutic opportunities.
    Keywords:  Notch; WNT; gene perturbation; intratumoral heterogeneity; lineage ablation; lineage tracing; pancreas cancer; tissue organization
    DOI:  https://doi.org/10.1016/j.devcel.2026.02.017
  2. Redox Biol. 2026 Mar 19. pii: S2213-2317(26)00128-X. [Epub ahead of print]92 104130
    Copper deprivation reprograms antioxidant defense to suppress ferroptosis via SLC7A11.
    Qian Xue, Ziyuan Chen, Jiao Yang, Kaixuan Ren, Xiaofen Li, Xi Chen, Ding Yan, Yuan Wang, Daolin Tang, Jinbao Liu, Xin Chen.
      Copper is an essential trace element that governs diverse cellular functions and influences cell fate. However, how cells adapt to copper deprivation remains poorly understood. Here, we identify a copper-ferroptosis regulatory axis mediated by the cystine transporter SLC7A11. We show that copper loss, induced either by silencing of the copper importer SLC31A1 or by pharmacological chelation, leads to a marked upregulation of SLC7A11. This adaptive response enhances glutathione synthesis, bolsters antioxidant defenses, and protects cells from ferroptosis. Mechanistically, copper deprivation activates AMPK, which stabilizes the transcription factor NRF2 to drive SLC7A11 expression. Functionally, SLC31A1 depletion diminishes ferroptosis-dependent tumor suppression in xenograft models, while dietary copper restriction alleviates ferroptosis-mediated pancreatic injury in experimental acute pancreatitis. Together, these findings reveal copper deprivation as a robust condition driving ferroptosis resistance and suggest that dietary or pharmacological copper modulation could provide new strategies to fine-tune ferroptosis in cancer and tissue injury.
    Keywords:  AMPK; Copper; Ferroptosis; NRF2; SLC31A1; SLC7A11
    DOI:  https://doi.org/10.1016/j.redox.2026.104130
  3. Trends Cancer. 2026 Mar 26. pii: S2405-8033(26)00032-4. [Epub ahead of print]
    Dissecting histological transformation.
    Ethan M Earlie, Eric E Gardner, Harold Varmus, Ashley M Laughney.
      The adaptive nature of cancer is a major obstacle limiting durable treatment responses. Histological transformation (HT) is a process whereby one cancer changes into a categorically different tumor type, often following treatment with targeted therapy. Best characterized in lung and prostate adenocarcinomas, HT is particularly disconcerting because the resultant cancer no longer depends on the initial oncogenic driver program, is therapeutically recalcitrant, and is often highly metastatic. Partly because HT is technically difficult to study, this process remains poorly described. As newer therapies broaden the scope of oncogenic drivers that can be targeted, HT may become more prevalent, highlighting the need for further research to dissect these phenomena. We propose that modern experimental and analytical tools present an opportunity to advance our understanding and improve our clinical management of histologically transforming cancers.
    Keywords:  acquired resistance; cellular adaptation; histological transformation
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.001
  4. Nat Metab. 2026 Mar;8(3): 587-603
    PLIN5 phosphorylation orchestrates mitochondria lipid-droplet coupling to control hepatic lipid flux and steatosis.
    Sun Woo Sophie Kang, Lauryn A Brown, Colin B Miller, Katherine M Barrows, Jihye L Golino, Hanyang Liu, Constance M Cultraro, Daniel Feliciano, Mercedes B Cornelius-Muwanuzi, Kirsten Remmert, Jonathan M Hernandez, Andy D Tran, Michael Kruhlak, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      Steatotic liver disease is common, yet the mechanisms by which hepatocytes cope with surges in dietary fatty acids remain unclear. Here we use single-cell tissue imaging (scPhenomics) and spatial proteomics to map lipid handling across dietary states. Fasting remodeled mitochondria and lipid droplets (LDs), increasing mitochondria-LD contacts, whereas contacts were infrequent in Western diet (WD)-fed male mice. Fasting also elevated perilipin-5 (PLIN5), a mediator of mitochondria-LD tethering. PLIN5 overexpression modulated contact formation in a phosphorylation-dependent manner: the S155A variant enhanced organelle contacts and LD expansion, whereas the S155E variant reduced contacts and yielded fewer, smaller LDs. Overexpression of the S155A variant in WD reduced lipotoxicity. These data reveal an adaptive organelle-interaction program that channels lipids during nutrient stress and is attenuated by an obesogenic diet. Our work establishes scPhenomics for spatially resolved cell-state analysis and identifies PLIN5 phosphorylation as a lever to tune hepatocyte lipid flux, suggesting therapeutic potential for targeting mitochondria-LD coupling.
    DOI:  https://doi.org/10.1038/s42255-026-01476-1
  5. bioRxiv. 2026 Mar 04. pii: 2026.03.03.709279. [Epub ahead of print]
    Membrane Curvature Activates Src kinase and Promotes Metastatic Cancer Cell Survival.
    Wei Zhang, He You, Xinzhi Zou, Chih-Hao Lu, Xingyuan Zhang, Anna Amine, Zeinab Jahed, Michael Z Lin, Bianxiao Cui.
      Src family kinases (SFKs) play key roles in cancer metastasis. While SFKs are classically regulated by cell adhesions and transmembrane receptors, how they become activated following tumor cell detachment remains unclear. Here, we report curvature-induced kinase activation (CIKA), a distinct mechanism through which plasma membrane curvature directly promotes Src activation. Mechanistically, membrane curvature promotes the oligomerization of TOCA-family curvature-sensing proteins, inducing local biomolecular condensation. These condensates recruit Src, stabilize its open conformation, and exclude the negative regulator Csk, converting curved membrane domains into discrete kinase activation hubs. Disruption of CIKA using TOCA mutants inhibits curvature-induced Src activation and selectively impairs the viability of detached but not adherent cells. Functionally, curvature-induced Src activation promotes anchorage-independent survival, and its disruption suppresses metastatic colonization in xenograft mouse models. These findings reveal membrane curvature as a biophysical activator of Src and suggest CIKA inhibition as a potential therapeutic strategy to target metastatic cancer cells.
    DOI:  https://doi.org/10.64898/2026.03.03.709279
  6. bioRxiv. 2026 Feb 07. pii: 2026.02.05.703986. [Epub ahead of print]
    SenCat: Cataloging human cell senescence through multiomic profiling of multiple senescent primary cell types.
    Carlos Anerillas, Gisela Altés, Katarína Grešová, Dimitrios Tsitsipatis, Krystyna Mazan-Mamczarz, Reema Banarjee, Ana S G Cunningham, Martin Salamini-Montemurri, Jen-Hao Yang, Rachel Munk, Martina Rossi, Yulan Piao, Bradley Olinger, Quinn Strassheim, Jennifer L Martindale, Jinshui Fan, Chang-Yi Cui, Supriyo De, Delaney V Rutherford, Ying Hao, Ziyi Li, Jessica Roberts, Yue Andy Qi, Kotb Abdelmohsen, Rafael de Cabo, Allison B Herman, Manolis Maragkakis, Nathan Basisty, Myriam Gorospe.
      There is an urgent need to comprehensively catalog senescence markers across cell types in an organism in order to characterize 'senotypes' and senescent cell heterogeneity. Here, we profiled the transcriptomes and proteomes in 14 different primary human cell types undergoing over 30 senescence paradigms to create a senescence catalog we termed 'SenCat'. We found that, while senescent cells from all primary tissue types did not share a single unique marker, they did activate shared specific metabolic and damage-response pathways implicated in tissue repair. Machine learning analysis of the SenCat transcriptomic and proteomic datasets successfully identified independent sets of senescent human cells, and senescent-like cells in mouse lung and kidney. In sum, SenCat represents a much-needed resource to identify senescent cells across tissues in the body.
    HIGHLIGHTS: Identifying senescent cells in organisms in vivo remains a challengeWe created SenCat: a catalog transcriptomes and proteomes of senescent primary cellsMachine learning (ML) analysis of SenCat identified robust senescence scoresML-derived senescence scores uncovered senescent-like cell dynamics in vivo.
    DOI:  https://doi.org/10.64898/2026.02.05.703986
  7. Trends Cancer. 2026 Mar 24. pii: S2405-8033(26)00038-5. [Epub ahead of print]
    Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
    Hendrik A Messal, Larissa Mourao, Lea Dörner, Colinda L G J Scheele, Jacco van Rheenen.
      Understanding tumor initiation is crucial for early interception and prevention. Tumors arise from genetic alterations and microenvironmental changes that together create a niche for malignant growth. Previously, the spatiotemporal dynamics of tumorigenesis were difficult to study. Recent advances in high-resolution intravital microscopy, tissue clearing, and spatial molecular profiling enable direct visualization of mutated cells and clones within their microenvironment in situ. These tools transform tumor initiation from a theoretical construct into a mechanistically dissectible process. Here, we synthesize recent insights into how mutated clones expand or regress, how clonal dynamics drive transformation, and how niche signals shape tumor-initiating cell fate. We highlight key imaging innovations and outline limitations and opportunities for capturing tumor initiation in vivo.
    Keywords:  clonal dynamics; intravital microscopy; spatial transcriptomics; tissue clearing; tumor initiation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.007
  8. J Exp Med. 2026 May 04. pii: e20251228. [Epub ahead of print]223(5):
    Local gene editing of fibroblasts in tumors reveals a new cancer-associated fibroblast state.
    Nicholas F Kuhn, Itzia Zaleta-Linares, Kenneth H Hu, Tristan Courau, Brittany Davidson, Tammie Tam, Chih-Wei Chu, Maxime J Kinet, Michael D Rosenblum, Alexis J Combes, William A Nyberg, Justin Eyquem, Matthew F Krummel.
      Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships act locally. We optimized local gene editing of fibroblasts in mouse tumor models to investigate how fibroblast perturbations affect the tumor microenvironment (TME). By knocking out receptors Osmr, Tgfbr2, or Il1r1 on cancer-associated fibroblasts (CAFs), we uncover that TGFBR2 signaling loss induces the emergence of a new Col18a1hi CAF cell state that is associated with worse survival in pancreatic cancer patients. Combinatorial gene KOs in CAFs reveals a circuit where these Col18a1hi CAFs reshape the TME by recruiting Siglec-Fhi neutrophils via Cxcl5 expression, and where this Col18a1hi CAF cell state is dependent on TNFR1 and canonical Wnt signaling. Together, a fast, affordable, and modular engineering method is demonstrated, allowing discovery of modified fibroblast identities and local intercellular relationships in the TME.
    DOI:  https://doi.org/10.1084/jem.20251228
  9. Nat Med. 2026 Mar 25.
    Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: the phase 2 POLAR trial.
    Wungki Park, Catherine A O'Connor, Joanne F Chou, Marc Hilmi, Zeynep Tarcan, Carly Schwartz, Mary Larsen, Ramzi Homsi, Karthigayini Sivaprakasam, Shigeaki Umeda, Maria A Perry, Anna M Varghese, Kenneth H Yu, Fiyinfolu Balogun, Alice Zervoudakis, Seth S Katz, Tae-Hyung Kim, Ken Zhao, Allison L Richards, Nicolas Lecomte, Daniel Martin Muldoon, Elias Karnoub, Walid Chatila, Jessica Yang, Imane El-Dika, Devika Rao, Smita Joshi, Michael B Foote, Ryan Sugarman, James J Harding, Andrew S Epstein, David Kelsen, Sree Chalassani, Fergus Keane, Joshua D Schoenfeld, Anupriya Singhal, Erin Diguglielmo, Chaitanya Bandlamudi, Junmin Song, Hulya Sahin Ozkan, Junguei Hong, Haochen Zhang, Agustin Iii Cardenas, Maria Lao, Jerry Melchor, Ronak Shah, Wenfei Kang, Francesca Mazzoni, Kevin Soares, Mark Ta Donoghue, Ernesto Santos, Vineet Rolston, Marsha Reyngold, Alice Chia-Chi Wei, Murray Tipping, Olca Basturk, Michael Berger, Richard Kihn Do, Mark Schattner, William R Jarnagin, Nadeem Riaz, Vinod Balachandran, Dana Pe'er, Marinela Capanu, Christine Iacobuzio-Donahue, Eileen M O'Reilly.
      Homologous recombination deficiency (HRD) arising from BRCA1or BRCA2 or PALB2 mutations confers sensitivity to platinum chemotherapy and PARP inhibition in pancreatic cancer (PC) and may enable prolonged disease control with immune checkpoint blockade (ICB). The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib following platinum-based chemotherapy in biomarker-stratified metastatic PC. Sixty-three participants were enrolled into three cohorts: cohort A (BRCA1/BRCA2-mutated or PALB2-mutated HRD, n = 33), cohort B (non-core HRD, n = 15) and cohort C (platinum sensitive, HRD-wild type, n = 15). Cohort A used a two-stage design with co-primary endpoints of at least 43% Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate (ORR) and at least 77% 6-month progression-free survival (PFS) rate. Among RECIST-evaluable participants in cohort A (n = 20), ORR was 35% (95% confidence interval (CI): 15-59%), whereas 6-month PFS rate in the full cohort (n = 33) was 64% (95% CI: 49-82%), not meeting the primary endpoint. At a median follow-up of 37 months (95% CI: 27-47), median PFS and overall survival (OS) for cohort A were 8.3 (95% CI: 5.3-not reached (NR)) and 28 (95% CI: 12-NR) months, with 2-year and 3-year OS rates of 56% (95% CI: 41-76%) and 44% (95% CI: 28-69%), respectively. In cohorts B and C, ORR was 8% (95% CI: 0-38%) and 14% (95% CI: 2%-43%); median PFS was 4.8 (95% CI: 4.0-12) and 3.3 (95% CI: 1.9-4.8) months; and median OS was 18 (95% CI: 13-NR) and 10 (95% CI: 8.9-24) months, respectively. Preplanned translational analyses showed that circulating tumor DNA response, increased tumor-infiltrating lymphocytes and enrichment of frameshift indel neoantigens were associated with durable clinical benefit. These data suggest that a subset of HRD PC may derive prolonged benefit from PARP-ICB maintenance and support further development of biomarker-guided precision immunotherapy strategies in PC. ClinicalTrials.gov identifier: NCT04666740 .
    DOI:  https://doi.org/10.1038/s41591-026-04299-5
  10. Trends Cell Biol. 2026 Mar 25. pii: S0962-8924(26)00033-4. [Epub ahead of print]
    Repair condensates and lipid domains in lysosome integrity.
    Claudio Bussi, Weiping Li.
      Lysosomes are sophisticated signaling hubs whose function depends on membrane integrity. A breach of this barrier, known as lysosomal membrane permeabilization, triggers inflammation and cell death, driving pathologies from lysosomal storage disorders to neurodegeneration. Cells counter membrane damage with diverse repair mechanisms, including endosomal sorting complexes required for transport machinery, sphingomyelin scrambling, annexin-mediated scaffolding, lipid transport, and stress granule plugging. This diversity suggests singular strategies are insufficient, posing an 'orchestration challenge' regarding precise initiation, spatial organization, and temporal coordination. This opinion article proposes that biomolecular condensation, initiated by damage cues, acts as a primary organizing principle. We suggest lysosomal injury nucleates de novo 'repair condensates' that stabilize compromised membranes and serve as recruitment and organizational hubs for repair machinery.
    Keywords:  biomolecular condensates; lipids; lysophagy; lysosomes; membrane damage
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.002
  11. Mol Cancer. 2026 Mar 27.
    Spatially-resolved subtype progression reveals metabolic vulnerabilities in pancreatic ductal adenocarcinoma.
    Alexandra Maria Schmitt, Fabio Bennet Gätje, Michelle Yi Ran Tran, Teona Midelashvili, Xingbo Xu, Johannes Robert Fleischer, Henrik Spahn, Kelvin Lai, Tobias Tacke, Sara Younes, Anne Mittlmeier, Olaf Schulze, Kaida Hasanovic, Moritz Leander Blume, Sara Marie Rotter, Theon Robin Tesch, Carolin Schneider, Jovan Todorovic, Hanibal Bohnenberger, Stefan Kueffer, Philipp Ströbel, Argyris Papantonis, Ulrich Sax, David Agorku, Silvia Rüberg, Fabio El Yassouri, Rajeshwaran Purushothaman, Svenja Warratz, Nathalia Ferreira, Günter Schneider, Sebastian Igelmann, Melanie Planque, Sarah-Maria Fendt, Michael Ghadimi, Elisabeth Hessmann, Lutz Ackermann, Tiago De Oliveira, Lena-Christin Conradi.
      
    Keywords:  Classical and basal subtypes; Classical-to-basal trajectory; Glycolysis; Metabolism; PFKFB3; Pancreatic ductal adenocarcinoma; Spatial transcriptomics; Subtype-agnostic targets
    DOI:  https://doi.org/10.1186/s12943-026-02628-3
  12. Methods Enzymol. 2026 ;pii: S0076-6879(26)00011-X. [Epub ahead of print]728 327-345
    Real-time measurement of the ATG8 lipidation reaction by fluorescence spectroscopy.
    Wenxin Zhang, Sharon A Tooze, Taki Nishimura.
      Autophagy is a highly conserved intracellular degradation pathway, in which damaged organelles and/or dysfunctional cytosolic components are enveloped via double-membraned autophagosomes and subsequently delivered to lysosomes for degradation. The ubiquitin-like ATG8 family proteins (LC3s and GABARAPs) are covalently conjugated to phosphatidylethanolamine (PE) on autophagic membranes via ubiquitin-like conjugation systems, a process known as ATG8 lipidation. Lipidated ATG8 is the most widely used membrane marker for autophagosomes, and its flux is commonly used as a readout for autophagy activity. In vitro reconstitution of the ATG8 lipidation reaction is well-established, and the end-point reaction is typically resolved by SDS-PAGE. This endpoint readout is not suitable to monitor the kinetics of this reaction, and tools to study this process have been lacking. Here, we describe a real-time assay to measure the ATG8 lipidation reaction. This approach not only reveals the subsequential formation of covalently bound intermediates of ATG8 with the E1 (ATG7) and E2 (ATG3) enzymes, as well as ATG8-PE itself, but also provides insights into the interaction interface of ATG8 with proteins and membranes during the conjugation reaction.
    Keywords:  3-diazol-4-yl (NBD); 7-nitrobenz-2-oxa-1; ATG8 lipidation; Autophagy; Fluorescence spectroscopy; Liposomes; Site-specific labeling; in vitro reconstitution
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.011
  13. N Engl J Med. 2026 Mar 25.
    Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer.
    Wungki Park, Anup Kasi, Alexander I Spira, Luis Paz-Ares Rodríguez, Benjamin O Herzberg, Meredith S Pelster, Anthony W Tolcher, Yasutoshi Kuboki, Shigehisa Kitano, Hirokazu Shoji, Judy S Wang, Jordan D Berlin, Antoine Hollebecque, Patricia LoRusso, Christos Fountzilas, Philippe A Cassier, Tomohiro Nishina, Daisuke Sakai, Chiaki Inagaki, Daniel Morgensztern, Makoto Ueno, Minkyu Jung, Sang-We Kim, Pasi A Jänne, Antoine Italiano, Benoît You, T Macarulla, Hisaki Fujii, Aditya Shetty, Ying Lu, Daniel Cui, Shilpa Kadam, Stanley C Gill, Junko Toyoshima, Takeshi Saito, Jonathan W Goldman.
       BACKGROUND: The KRAS p.G12D variant occurs in 5% of patients with non-small-cell lung cancer (NSCLC) and is the most common substitution variant in pancreatic ductal adenocarcinoma, occurring in 40% of patients, but no targeted therapies directed against this variant are currently approved for clinical use. Setidegrasib (ASP3082) is a first-in-class KRAS G12D-targeted protein degrader.
    METHODS: We conducted this phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. The primary objectives were to evaluate the safety profile, as indicated by dose-limiting toxic effects and adverse events (the primary end points), and to determine the phase 2 dose. Setidegrasib was administered intravenously once weekly at doses of 10 to 800 mg.
    RESULTS: Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as the phase 2 dose, adverse events occurred during treatment in all the patients, with events of grade 3 or higher in 42%. Treatment-related adverse events occurred in 93% of the patients; the most common were transient infusion-related reactions (in 80%) and nausea (in 30%). Adverse events led to discontinuation in 2 patients. Among the 45 patients with NSCLC who received the 600-mg dose, 36% (95% confidence interval [CI], 22 to 51) had a partial response, the median progression-free survival was 8.3 months (95% CI, 4.1 to could not be estimated), and the estimated 12-month overall survival was 59% (95% CI, 40 to 74). Among the 21 patients with metastatic pancreatic ductal adenocarcinoma who received the 600-mg dose as second- or third-line treatment (of whom 67% received setidegrasib as third-line treatment), 24% (95% CI, 8 to 47) had a response, the median progression-free survival was 3.0 months (95% CI, 1.4 to 6.9), and the median overall survival was 10.3 months (95% CI, 4.2 to 13.0).
    CONCLUSIONS: Setidegrasib was associated with antitumor activity and a low incidence of treatment discontinuation due to adverse events in patients with previously treated advanced KRAS p.G12D-mutated NSCLC or pancreatic ductal adenocarcinoma. (Funded by Astellas Pharma; ClinicalTrials.gov number, NCT05382559.).
    DOI:  https://doi.org/10.1056/NEJMoa2600752
  14. Cancer Cell. 2026 Mar 26. pii: S1535-6108(26)00156-X. [Epub ahead of print]
    Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer.
    Elijah Kirschstein, Olivia Harder, Jordan Krull, Madison Sikorski, Shrijan Khanal, Morgan Mack, Carl F Ware, Elizabeth Evans, Michael J Gough, Qin Ma, Wei Chen, Kristina H Young, Andrew J Gunderson.
      Pancreatic ductal adenocarcinoma (PDAC) is strongly resistant to immunotherapy. However, recent evidence shows that some PDAC tumors contain tertiary lymphoid structures (TLSs) associated with improved survival. Why TLS forms in some tumors but not others remains elusive. Using a lymphotoxin beta receptor (LTBR) agonist, we observe the induction of TLS-aggregates in some murine PDAC tumor models but not others. The phenotypes of cancer-associated fibroblasts (CAFs) in TLS-resistant models are myofibroblastic (myCAF), whereas TLS-permissive models are enriched with reticular-CAF (rCAF) subsets. Differentiation into myCAF blocks the LTBR-mediated upregulation of chemokines and lymphocyte migration toward fibroblasts. Inhibiting the transforming growth factor β (TGFβ) receptor, combined with LTBR agonism, promotes TLS formation and T cell-dependent tumor control. In patient tumors, rCAF are proximal to TLS, while myCAF are distally located. These data indicate that myCAF represses rCAF programming critical for TLS formation but can be therapeutically remodeled to promote immune control of PDAC tumors.
    Keywords:  cancer associated fibroblasts; pancreatic cancer; tertiary lymphoid structures; tumor immunity
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.004
  15. bioRxiv. 2026 Mar 18. pii: 2026.03.16.711688. [Epub ahead of print]
    Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade.
    Xiaoshuang Wang, Zi Wang, Yuqi Guo, Fangxi Xu, Jinhui Zhu, Scott C Thomas, Deepak Saxena, Jinghang Xie, Xin Li.
      Resistance to immune checkpoint inhibition remains a major barrier in pancreatic cancer treatment. Here, we show that concurrent administration of probiotics restores sensitivity to anti-PD-1 therapy in pancreatic cancer mouse models. Mice treated with the combination of anti-PD-1 and probiotics demonstrate robust tumor control, accompanied by enrichment of microbial pathways governing cysteine biosynthesis, elevated serum cysteine levels, and increased T cell function. Serum cysteine levels, rather than intratumoral cysteine concentrations, inversely correlate with tumor burden. Functionally, cysteine directly promotes T cell survival, activation, and cytotoxicity while its restriction induces uncoupled transcriptional-translational stress and impairs T cell function. Oral cysteine supplementation synergizes with anti-PD-1 therapy in pancreatic cancer mice, reducing tumor burden and enhancing intratumoral T cell activation, phenocopying probiotics-mediated immune restoration. These findings suggest systemic cysteine availability as a tractable metabolic target to enhance cancer immunotherapy.
    DOI:  https://doi.org/10.64898/2026.03.16.711688
  16. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70260
    Single-Cell RNA-Sequencing Reveals Cachectic Satellite Cell Population in Muscle of Male Mice With Cancer Cachexia.
    Alex Brown, Nicolás Collao, Aisha Saleh, Natasha Strong, Michael De Lisio, Nadine Wiper-Bergeron.
       BACKGROUND: Cancer cachexia leads to decreases in body mass, lean mass and fat mass, decreased therapeutic potential and ~20% of cancer-related deaths. While several studies have demonstrated changes to components of the muscle microenvironment with cancer cachexia, none have comprehensively assessed changes to cellular dynamics across the duration of cachexia development.
    METHODS: Single-cell RNA-sequencing was performed on hindlimb muscles of male mice with 2-, 2.5- and 3.5-week subcutaneous Lewis-lung carcinoma tumours. Cell population changes were confirmed with flow cytometry.
    RESULTS: Body mass (-0.51 g; p = 0.0014) and lean mass (-0.85 g; p = 0.0134) were decreased at 2.5 weeks and were significantly lower than sham. Increases in fat mass were attenuated starting at 2 weeks (0.70 g; p = 0.0408) compared to sham (1.55 g), and muscle cross-sectional area decreased at 3.5 weeks (-14.81%; p = 0.0022) compared to sham. We report a novel cachexia-associated satellite cell subcluster, comprising 71.1% of the population at 3.5 weeks, corresponding with a +20.33% increase in cell size (p = 0.0266) and +19.73% increase in the proportion of activated PAX7+MYOD+ cells after 24 h cultured on individual myofibres (p = 0.0226). This cachexia-associated subcluster was also present in C26 tumour-bearing mice and had a unique gene expression signature compared to other muscle wasting disorders. The cachexia-associated subcluster was enriched for signalling pathways (IL-17, TNF, p53, NF-κB, FoxO, adipocytokines, NOD-like receptor, MAPK and JAK-STAT) implicated in satellite cell dysfunction in cancer cachexia. Prior to the emergence of cachexia-associated satellite cells, increases in CD11b+ (+928.01%; p < 0.0001), Ly6Clow (+1080.85%; p < 0.0001), Ly6Chigh (+920.33%; p = 0.0002), F4/80+CD206- (+299.22%; p = 0.0039), F4/80+CD206+ (+1466.40%; p < 0.0001) immune cell populations were observed at 2 weeks compared to sham and returned to baseline by 2.5 weeks. There was also an increase in PDGFRα+ fibro-adipogenic progenitors at 2 weeks (+53.44%; p = 0.0398) and decreased CD31+ endothelial cells at 2 weeks (-57.37%; p = 0.0014) and 3.5 weeks (-39.78%; p = 0.0213) compared to sham, with no change in ITGA7+ satellite cells (p = 0.4271). Cell communication analyses revealed a decline in cell communication with cancer cachexia in all cells except for monocytes/macrophages, and a decrease in cell adhesion-related signalling in cachexia-associated satellite cells, which is important for satellite cell differentiation, and may help to explain differentiation defects with cachexia.
    CONCLUSIONS: We describe a novel satellite cell subcluster unique to cachexia. We also identified increased immune cell and fibroadipogenic progenitor content and decreased endothelial cell content that precede muscle wasting with cancer, suggesting a role for these cell populations in satellite cell dysfunction and muscle atrophy in this condition.
    Keywords:  cancer cachexia; muscle atrophy; muscle satellite cells; single‐cell RNA sequencing; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70260
  17. Cell Death Discov. 2026 Mar 24.
    Redox cycling nitroxide limits cellular iron availability and selectively inhibits iron-sulfur cluster metabolism.
    Erdem M Terzi, Kenji M Fujihara, Marte Molenaars, Douglas E Biancur, Richard Possemato.
      Iron-sulfur clusters (ISCs) are redox active cofactors for essential proteins with diverse functions. We demonstrate that Tempol, a redox cycling nitroxide, limits iron bioavailability in a manner distinct from iron chelators, mainly via its effect on ascorbate and iron redox balance. This non-canonical iron limitation triggers upregulation of IRP2 and HIF1α, proteins whose degradation is ferrous iron-dependent, while disrupting ISC synthesis only in a subset of cell lines. Suppression of ISC synthesis inhibits ISC-dependent enzymes, destabilizes ISC proteins, and reduces cell viability, particularly in cells dependent on ISC protein ACO2. These effects are reversed by the reducing agent ascorbate, a cofactor required for multiple enzymes, such as the HIF1α prolyl hydroxylases. Tempol treatment also inhibits ferroptosis, an oxidative form of cell death catalyzed by reduced iron. These results demonstrate ascorbate and cellular iron redox state are essential in iron homeostasis, which is proposed to underlie pathological conditions from neurodegeneration to cancer.
    DOI:  https://doi.org/10.1038/s41420-026-03042-w
  18. Cell Death Discov. 2026 Mar 26.
    The role of NINJ1 in diseases.
    Shijun Bao, Fengxu Chen, Ziyi Guo, Wen Ding, Fu Gao, Jiaming Guo.
      Nerve injury-induced protein 1 (NINJ1) is a multifunctional membrane protein historically studied for its roles in nerve regeneration and cell adhesion. A groundbreaking study fundamentally revised our understanding by demonstrating that NINJ1 acts as the active executor of plasma membrane rupture in lytic cell death pathways such as pyroptosis and ferroptosis, establishing this final step as a biologically regulated process. Recent structural insights now reveal that NINJ1 adopts distinct molecular forms-including the full-length monomer, a soluble fragment, and a membrane-rupturing oligomer-which dictate its functional roles in adhesion, chemotaxis, and cell lysis. This revised understanding calls for a systematic integration of previous observations, particularly given NINJ1's context-dependent and often contradictory roles in inflammation, cancer, and tissue injury. Here, we review the structural basis of NINJ1 function, its pathological implications, and propose a unified structure-function model to reconcile its diverse phenotypes and bridge its traditional roles with its newly identified function in membrane rupture.
    DOI:  https://doi.org/10.1038/s41420-026-03064-4
  19. Mol Biol Cell. 2026 Mar 25. mbcE25120621
    Interplay between membrane protrusive activities and their adhesion strength regulates cell migration.
    Indranil Ghosh, Ditipriya Mallick, Ankita Sen, Anwesha Kar, Shilpak Chatterjee, Siddhartha Sankar Jana.
      Migratory cells can adopt membrane protrusions like blebbing or lamellipodia for efficient migration. The underlying mechanisms of how switching contributes to cell migration are not clearly understood. Here we found that nonmuscle myosin II (NM II) mediated blebbing to lamellipodia conversion (BLC) increased the speed of migration whereas lamellipodia to blebbing conversion (LBC) decreased it in various cells like cancerous cells, mesenchymal stem cells, and T-lymphocytes. Cells with lamellipodia had larger and greater number of focal adhesions compared with blebbing cells, suggesting a link between adhesion strength with membrane protrusions and migration. Migratory cells seeded on collagen I, but not on poly-L-lysine, exhibited a faster BLC and greater migration speed compared with cells seeded on an uncoated surface. Knockdown of integrinβ1 reduced cell migration but these cells were able to undergo conversion of membrane protrusions, albeit with a substantial delay. These findings suggest that cells can fine tune the migration strategy by controlling NM II-mediated protrusion switching and modulating integrin dependent adhesion strength. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-12-0621
  20. Cancer Discov. 2026 Mar 27.
    Senescent cancer-associated fibroblasts drive early-stage lymph node metastasis in pancreatic cancer through lactate-mediated metabolic-epigenetic rewiring.
    Tianxing Zhou, Jingrui Yan, Guohua Mao, Yu Zhang, Shangheng Shi, Tinghai Hu, Jingbo Xu, Yaqi Zhang, Zhi Ji, Qingxiao Fang, Zhaoyu Zhang, Zekun Li, Ziyun Liu, Yifei Wang, Hongwei Wang, Tiansuo Zhao, Song Gao, Xiuchao Wang, Chao Yang, Chongbiao Huang, Jing Liu, Antao Chang, Shengyu Yang, Jun Yu, Yukuan Feng, Rui Liu, Yongjie Xie, Bin Wang, Jihui Hao.
      Lymph node metastasis (LNM) in early-stage PDAC predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrated that senescent cancer-associated fibroblasts (senCAFs) drive lymphatic remodeling and LNM in early-stage PDAC. Mechanistically, senCAFs increased glucose metabolism and lactate production, which activated lactylation-mediated serine metabolism to protect lymphatic endothelial cells from oxidative stress. Moreover, we discovered CCR4+ Tregs from the draining lymph nodes accumulated around lymphatic vessels, which established an immunosuppressive peri-lymphatic niche. High throughput drug screening determined selective clearance of senCAFs via chidamide, attenuated tumor progression and improved chemo-immunotherapeutic efficacy. We subsequently initiated a clinical trial (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4) in metastatic PDAC patients and reported its preliminary promising results. Collectively, these findings reveal a closed link between cellular senescence and PDAC metastasis, offering the potential senolytic means to improve chemo-immunotherapy efficacy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1627
  21. Front Bioinform. 2026 ;6 1763403
    Chart builder: an interactive tool for user driven data visualization in the electron microscopy data bank.
    Neli Fonseca, Amudha Kumari Duraisamy, Zhe Wang, Sriram Somasundharam, Minoosadat Tayebinia, Lucas C de Oliveira, Miao Ma, Jack Turner, Ardan Patwardhan, Gerard J Kleywegt, Matthew Hartley, Kyle L Morris.
      The cryogenic sample-electron microscopy (cryoEM) field has generated significant amounts of 3D Electron Microscopy (3DEM) volumetric data and associated metadata, now comprehensively archived in the Electron Microscopy Data Bank (EMDB - www.emdatabank.org) and the Electron Microscopy Public Image Archive (EMPIAR - www.empiar.org). Harnessing the full potential of these resources requires robust, flexible, and publicly accessible tools for data exploration, analysis and retrieval. Here, we present Chart Builder, an interactive web-based platform that enables researchers to create customizable, publication-quality visualizations directly from archival metadata, validation assessments, and cross-reference annotations. Chart Builder integrates the same query-driven and flexible Solr search system as EMDB search, into a user interface with tools to assist users to filter, group, and compare data without programming expertise. It supports multiple chart types (including line, bar, area, scatter (2D and 3D), histogram, bubble, pie, geographic and Venn diagrams) with customizable axes, data series, and statistical operators. Users can apply global filters, define temporal, categorical, or custom query-based axes, and explore multi-dimensional relationships interactively. Chart data-points are linked to their underlying datasets, such that visualisation interaction opens entry-level or archive-level search results for inspection and datasets from charts may be exported in several ways. Findability, accessibility, interoperability and reusability of data are facilitated by these direct access and export mechanisms, including HTML embedding, persistent URL sharing and chart/data download options. By combining interactivity and ease of use with up-to-date access to the EMDB and EMPIAR archive metadata, both computational and experimental communities may explore and visualize current metadata and export to formats for further analysis or as publication-ready figures. Chart Builder promotes community-driven data analysis and empowers users to evaluate trends in the biological 3DEM field. Chart Builder is freely accessible and fully integrated into the EMDB website at https://www.ebi.ac.uk/emdb/statistics/builder/.
    Keywords:  FAIR (findable accessible interoperable andreusable) principles; cryoEM (cryo-electron microscopy); data repository; data visualization; graph
    DOI:  https://doi.org/10.3389/fbinf.2026.1763403
  22. Biomed Pharmacother. 2026 Mar 21. pii: S0753-3322(26)00290-8. [Epub ahead of print]198 119257
    Novel L1CAM-antibody drug conjugates exert potent anti-tumor activity in preclinical models of even advanced pancreatic cancer.
    Annika Brauer, Anne-Sophie Mehdorn, Jan-Paul Gundlach, Charlotte Hauser, Philipp Putze, Lea Stahmer, Rüdiger Braun, Rainer Heuchel, David Holthaus, Daniela Wesch, Christoph Röcken, Åsa Rosenquist, Christer Ericsson, Flavio Mehli, Anne Schmidt, Gunther Spohn, Anna Maxi Wandmacher, Susanne Sebens.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor 5-year overall survival. This can be mainly explained by late diagnosis mostly at advanced stages, excluding primary tumor resection as putative curative treatment, and a profound therapy resistance. L1 cell adhesion molecule (L1CAM) is upregulated in PDAC cells and associated with different hallmarks of cancer contributing to tumor progression and therapy resistance. Using L1CAM as tumor associated antigen, two antibody drug conjugates (ADC) targeting L1CAM were developed with different toxins as payload. Both L1CAM-ADC led to a L1CAM specific reduction in tumor cell growth of up to 60% in 2D PDAC cell models. A maximum therapeutic effect was observed when at least 50% of the PDAC cells expressed L1CAM. In 3D PDAC spheroids, MMAE conjugated L1CAM-ADC still showed strong therapeutic effects, while efficacy of SG3199 conjugated L1CAM-ADC was diminished. Co-culture of PDAC spheroids with pancreatic myofibroblasts did almost not impair L1CAM-ADC anti-tumor effects, while macrophages enhanced anti-tumor responses. Application of L1CAM-ADC as adjuvant or palliative treatment in clinically adapted PDAC mouse models exerted potent anti-tumor effects even with enhanced tumor burden. Adjuvantly applied, MMAE conjugated L1CAM-ADC efficiently reduced pancreatic relapses and peritoneal metastases, whereas SG3199 conjugated L1CAM-ADC less impacted pancreatic relapses, but almost completely eliminated liver and peritoneal metastases. In the palliative setting, both L1CAM-ADC reduced number and size of liver and peritoneal metastases. Overall, our results demonstrate strong anti-tumor effects of L1CAM-ADC underscoring their potential as immunotherapeutic approach in therapy of even advanced PDAC.
    Keywords:  ADC; CAF; Immunotherapy; Macrophages; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.biopha.2026.119257
  23. bioRxiv. 2026 Mar 02. pii: 2026.03.01.708804. [Epub ahead of print]
    Tmn blocks phage spread via plasmolysis and triggers synergistic defence responses.
    Yi Wu, Zhiying Zhang, Sofya K Garushyants, Ruizhe Li, Regan Doherty, James A Milton, Matthew J Cooper, Yilmaz Emre Gençay, Triana Amen, Somenath Bakshi, Dinshaw J Patel, Eugene V Koonin, Franklin L Nobrega.
      Membrane-associated phage defences remain poorly understood. Here we characterise Tmn, a YobI-family transmembrane P-loop NTPase that protects bacteria from phage infection by establishing a plasmolysis-associated antiviral state. Upon recognising phage T2 RIIB protein, Tmn enhances ATP turnover and selectively exports Mg2+, causing rapid cytoplasmic collapse that arrests phage replication without detectable membrane depolarisation or gross leakage of the cell content. Cryo-electron microscopy shows that Tmn assembles into a decameric membrane complex with extended cytosolic arms, an uncommon architecture among P-loop NTPases. The cytosolic arms, including a solenoid-like repeat domain, mediate trigger interaction and determine specificity. In addition to its primary defence function, Tmn-driven ATP collapse activates otherwise silent ATP-depletion-sensing defences, including Gabija and Septu type I, providing a mechanistic basis for synergy among defence systems and limiting secondary phage spread. These findings demonstrate that Tmn is a membrane-integrated sensor-effector that couples phage recognition to metabolic collapse and coordinated multi-layered immunity.
    DOI:  https://doi.org/10.64898/2026.03.01.708804
  24. Neuron. 2026 Mar 25. pii: S0896-6273(26)00089-9. [Epub ahead of print]
    Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions.
    Emma K Theisen, Irma Magaly Rivas-Serna, Peiwen Cheng, Ryan J Lee, Connon I Thomas, Anza Darehshouri, Taylor R Jay, Govind Kunduri, Tasha T Nguyen, Vera Mazurak, M Thomas Clandinin, Thomas R Clandinin, John P Vaughen.
      The complex morphologies of neurons and glia emerge through profound changes in membrane lipids and proteins during development. Lysosomes are central regulators of membrane remodeling, and mutations that affect lipid turnover in lysosomes are frequently associated with neurological disease. However, how these lysosomal functions might shape brain development remains incompletely understood. By analyzing lipid levels in the Drosophila brain, we discover transient increases in specific sphingolipids during development. This lipid bolus reflects biosynthetic inputs from both neurons and glia, and requires lysosomal catabolism for mature neuronal physiology to emerge. Remarkably, sphingolipid catabolism in glia is substantially driven by the phagolysosomal salvage of neuronal membranes to produce very long-chain ceramide phosphoethanolamine (CPE) lipids. CPE lipids are cell-autonomously required for glial autophagy and ramification into synaptic regions, and a genetic CPE biosensor localizes to infiltrated glial processes. Thus, developmentally regulated lysosomal activity obligately couples neuron-glia metabolic interactions to program dynamic glial morphogenesis.
    Keywords:  GBA; LSDs; VLCFAs; arborization; autophagy; ceramide phosphoethanolamine; glia; glucocerebrosidase; lysosomal storage diseases; neurodevelopment; phagocytosis; sphingolipids; very long chain fatty acids
    DOI:  https://doi.org/10.1016/j.neuron.2026.02.006
  25. bioRxiv. 2026 Mar 04. pii: 2026.03.02.706451. [Epub ahead of print]
    Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
    Clemens Hinterleitner, Valentin J A Barthet, Hailey V Goldberg, Kristen C Vogt, Ana Marie Perea, Stephen Ruiz, Logan R Hillger, Domhnall McHugh, Yu-Jui Ho, Almudena Chaves-Perez, Maria Skamagki, Sara Flowers, Natasha Rekhtman, Xueqian Zhuang, Gabriel Dessotti Barretto, Xiang Li, Jadae T Watson, Wei Luan, Janelle Simon, Tuomas Tammela, Rui Gardner, Charles M Rudin, Paul B Romesser, Matthew J Bott, Aveline Filliol, Daniel A Heller, Scott W Lowe.
      Fibrotic remodeling of tissues and tumors establishes immune-suppressive microenvironments that drive organ dysfunction and, in cancer, limit responses to immunotherapy. Cells exhibiting features of cellular senescence are conserved drivers of fibrotic remodeling and thus represent therapeutic targets, yet senescent states are heterogeneous and can exert both beneficial and pathogenic effects, complicating therapeutic intervention. Here, we show that P-selectin is selectively expressed by subsets of senescent-like cells in fibrotic tissues and fibrotic tumor microenvironments. Leveraging fucoidan-based nanoparticles that bind P-selectin, we develop senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated cell states. SMNPs exhibit potent antifibrotic and immunomodulatory activity while markedly improving therapeutic index. Mechanistically, we identify a pathogenic, immune-suppressive macrophage population as a principal functional target of SMNPs in vivo. In fibrotic tumors, niche remodeling restores immune infiltration and sensitizes tumors to immune checkpoint-based therapies. More broadly, SMNPs establish a generalizable nanotherapeutic strategy for selectively targeting pathogenic senescent cell subsets across fibrotic disease and cancer.
    DOI:  https://doi.org/10.64898/2026.03.02.706451
  26. Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00235-4. [Epub ahead of print]45(4): 117157
    Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.
    Jong Woo Kim, Seo Young Jang, Yeon Jin Roh, Yeajin Ju, Ju-Bin Kang, Byung-Sun Park, Ji-Yoon Lee, Min Wook Kim, Byung Jun Jeong, Woosung Jung, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Tackhoon Kim, Yun Pyo Kang, Hee Min Yoo, Chuna Kim, Scott J Dixon, Dong Wook Choi, Geum-Sook Hwang, Eun-Woo Lee.
      Ferroptosis is a lipid peroxidation-induced cell death mechanism that is regulated by amino acid metabolism. Cystine deprivation induces ferroptosis, but ferroptosis execution requires other amino acids. While methionine contributes to several metabolic pathways, including transsulfuration (TS), its role in ferroptosis remains controversial. Here, we report that methionine is required for ferroptosis triggered by cysteine deprivation. Notably, the TS pathway and methionine cycle in lung cancer cells are largely inactive, and methionine is instead funneled into polyamine synthesis via the methionine salvage route. Methionine depletion provokes metabolic shifts that dampen glutamine catabolism via the glutamine-methionine bi-cycle. Furthermore, methionine depletion alters phospholipid metabolism by promoting ACSL4 degradation, limiting polyunsaturated fatty acid (PUFA) incorporation into phospholipids. The methionine cycle intermediate S-adenosylmethionine (SAM) supplementation is sufficient to restore the perturbed metabolic state and ferroptosis sensitivity. Taken together, the results of this study highlight methionine as a key coordinator of ferroptosis through dynamic metabolic remodeling.
    Keywords:  ACSL4; CP: metabolism; CP: molecular biology; ferroptosis; glutaminolysis; methionine; methionine salvage pathway; phospholipid metabolism; transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.celrep.2026.117157
  27. Elife. 2026 Mar 23. pii: RP105523. [Epub ahead of print]14
    The cytoplasm of living cells can sustain transient and steady intracellular pressure gradients.
    Majid Malboubi, Mohammad Hadi Esteki, Malti B Vaghela, Lulu I T Korsak, Ryan J Petrie, Emad Moeendarbary, Guillaume Charras.
      Understanding the physical basis of cellular shape change in response to both internal and external mechanical stresses requires characterisation of cytoplasmic rheology. At subsecond time-scales and micron length-scales, cells behave as fluid-filled sponges in which shape changes necessitate intracellular fluid redistribution. However, whether these cytoplasmic poroelastic properties play an important role in cellular mechanical response over length- and time-scales relevant to cell physiology remains unclear. Here, we investigated whether and how a localised deformation of the cell surface gives rise to transient intracellular flows spanning several microns and lasting seconds. Next, we showed that pressure gradients induced in the cytoplasm can be sustained over several minutes. We found that stable pressure gradients can arise from the combination of cortical tension, cytoplasmic poroelasticity, and water flows across the membrane. Overall our data indicate that intracellular cytosolic flows and pressure gradients may play a much greater role than currently appreciated, acting over time- and length-scales relevant to mechanotransduction and cell migration, signifying that poroelastic properties need to be accounted for in models of the cell.
    Keywords:  AFM; cytoplasm; cytoskeleton; human; membrane transport; physics of living systems; poroelasticity; pressure
    DOI:  https://doi.org/10.7554/eLife.105523
  28. Anticancer Res. 2026 Apr;46(4): 1819-1831
    Establishment of Gemcitabine-resistant Mouse Pancreatic Ductal Adenocarcinoma Cell Line and Possible Therapeutic Agents.
    Kumiko Miyashita, Kimihiro Yamashita, Makoto Miyoshi, Takaaki Nishiyama, Yuki Ise, Shun Ohsaka, Kazuya Shimizu, Noriyuki Nishimura, Yuichi Hori.
       BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to gemcitabine (GEM) resistance. This study aimed to establish a clinically relevant immunocompetent model to identify novel mediators of acquired GEM resistance.
    MATERIALS AND METHODS: Metastatic PDAC (mPDAC) cells, generated from CD133-positive pancreatic stem cells (mutant Trp53, Cdk4, Kras), were subjected to chronic in vivo GEM selection to establish a line with reduced sensitivity (mPDAC-R).
    RESULTS: mPDAC-R exhibited sustained growth under GEM treatment, alongside enhanced invasiveness and metastatic potential. Transcriptomic profiling identified monoamine oxidase B (MAOB) as an up-regulated mediator. Pharmacological inhibition of MAOB significantly suppressed proliferation and tumor growth in both mPDAC-R and human PDAC cell lines.
    CONCLUSION: We established a novel GEM-resistant mPDAC model and identified MAOB as a promising therapeutic target. These findings provide a rationale for targeting MAOB-driven survival signals to overcome chemoresistance in refractory pancreatic cancer.
    Keywords:  CD133; Pancreatic ductal adenocarcinoma; cancer stem cell; gemcitabine resistance; monoamine oxidase B
    DOI:  https://doi.org/10.21873/anticanres.18076
  29. bioRxiv. 2026 Mar 16. pii: 2026.03.12.711465. [Epub ahead of print]
    Biophysical trade-offs in antibody evolution are resolved by conformation-mediated epistasis.
    Cole R Tharp, Claudio Catalano, Anthony Khalifeh, Sam Ghaffari-Kashani, Ruimin Huang, Gyunghoon Kang, Giovanna Scapin, Angela M Phillips.
      Protein evolution is constrained by multidimensional biophysical factors, in which mutations that enhance one property often compromise another. Antibodies represent an extreme case: they evolve rapidly to bind diverse antigens, yet mutations that improve affinity can disrupt folding, reduce cell-surface trafficking, or promote self-reactivity, and are typically selected against during affinity maturation. Though biophysical characterization of individual antibodies suggests that such trade-offs are pervasive, their impact on antibody evolutionary trajectories remains unclear, in part because existing high-throughput biophysical methods rely on heterologous systems that are often poorly suited for human proteins. Here, we develop a high-throughput platform to quantify multiple biophysical parameters of large libraries of full-length proteins that are natively synthesized, processed, and displayed on human cells. We apply this approach to a human antibody lineage that matures to recognize divergent SARS-CoV-2 variants by measuring the surface expression, antigen affinity, and self-reactivity for all 2^13 possible evolutionary intermediates between the unmutated and mature sequences. These measurements reveal that mutations differentially affect these biophysical properties - in some cases, improving one property at the expense of another. We leverage these data to compute the likelihood of all possible evolutionary paths, finding that very few paths can navigate these multidimensional requirements. The few accessible paths acquire mutations in a specific order that either circumvent trade-offs between biophysical properties or offset deleterious effects on one property with beneficial effects on another. By determining the structures of the ancestral and evolved antibodies, we find that these coordinated mutational effects arise from a conformational rearrangement that alleviates steric clashes and reshapes the biophysical landscape, enabling otherwise inaccessible mutational paths. Together, this work defines the multidimensional biophysical constraints and structural mechanisms that govern antibody evolution and establishes a general framework for mapping and predicting the biophysical effects of mutations in human proteins.
    DOI:  https://doi.org/10.64898/2026.03.12.711465
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