bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–03–15
forty-four papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma.
  2. Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting.
  3. Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
  4. Extracellular Matrix Sensing Controls Autophagy in Pancreatic Cancer.
  5. Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
  6. Mechanoresilience of lysosomes conferred by TMEM63A.
  7. Fat bolsters tumours against ferroptosis.
  8. Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
  9. Correlation between inflammation, vascularization, adipocyte percentage and exocrine cell percentage at the resection margin and the postoperative pancreatic fistula rate after distal pancreatectomy.
  10. Inactivation of CDKN2AARF Promotes p53-Independent Remodeling of the PDAC Tumor Microenvironment.
  11. Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer.
  12. Peritumoural adipose tissue promotes ferroptosis resistance by 3-hydroxykynurenine-mediated suppression of ferritinophagy.
  13. Ageing promotes metastasis via activation of the integrated stress response.
  14. Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
  15. Breaking cellular boundaries: molecular mechanisms of tunneling nanotube formation and fusion.
  16. A randomized phase II trial of gemcitabine, nab-paclitaxel, cisplatin with or without a medically supervised ketogenic diet for patients with metastatic pancreatic cancer.
  17. cAMP and mitochondrial dysfunction in cancer cachexia.
  18. Intra- and inter-organ communications in aging and cancer: Local and global spatial perspectives.
  19. Accelerated discovery of cell migration regulators using label-free deep learning-based automated tracking.
  20. Protocol to measure protein half-life in cell culture using heavy water.
  21. Large-scale identification of plasma membrane repair proteins revealed spatiotemporal cellular responses to plasma membrane damage.
  22. Impact of Vitamin D Status on Pancreatic Cancer Risk and Outcomes.
  23. Adhesion forces between macrophages and cancer cells promote early tumor development.
  24. Overcoming adaptive resistance to KRASG12D blockade in pancreatic cancer through vertical pathway inhibition.
  25. The Roles of SQSTM1/p62 in Selective Autophagy and Oncogenic Signaling.
  26. Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.
  27. AI might be the next stage of our natural evolution: A cancer neuroscience perspective.
  28. The Lethal Symbiont: Exploring the Pathophysiology of Cancer.
  29. KRAShing pancreatic cancer before takeoff.
  30. Time-resolved functional genomics using deep learning reveals global hierarchical control of autophagy.
  31. TOLLIP targets GSDME-NT-carrying endocytic vesicles for autophagy to regulate pyroptosis and chemotherapy efficacy.
  32. Early cellular plasticity promotes progression and dissemination in pancreatic adenocarcinoma.
  33. Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer.
  34. Protocol for immunofluorescence detection and quantitative analysis of pH-dependent transcriptional condensates.
  35. Arp2/3 complex and β1 integrin drive an invasive front through extracellular matrix adaptation in pancreatic cancer.
  36. Scalable analysis of whole slide spatial proteomics with Harpy.
  37. Systematic and Quantitative Investigation of Newly Synthesized Proteins Reveals Distinct Ion Homeostasis and Mitochondrial Changes between Cuproptosis and Ferroptosis in Human Cells.
  38. Wash-Free Multi-Target Super-Resolution Microscopy With Photocaged DNA Labels.
  39. Bringing magnetofluorescent proteins into the cell.
  40. Multilevel metabolic adaptation to exercise training.
  41. Assembly Module-Empowering Lipid-Prodrug Nanoamplifier for Enhancing Ferroptosis-Driven Cancer Treatment.
  42. Decoding GPX4 regulation in ferroptosis: mechanisms and therapeutic implications.
  43. Healing Wounds.
  44. STHELAR, a multi-tissue dataset linking spatial transcriptomics and histology for cell type annotation.
  1. Science. 2026 Mar 12. 391(6790): 1161-1166
    Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma.
    Minh T Than, Lucie Dequiedt, Rina Sor, Shreya Nair, Nune Markosyan, Emma E Furth, Chenghua Yang, Courtney Ray-Fofana, Marie Menard, Elsa Quintana, A Cole Edwards, Connor J Hennessey, Austin L Good, Liz Quinones, Yunseo Hwang, Cynthia Clendenin, Ashley L Kiemen, Robert H Vonderheide, Ben Z Stanger.
      Transformation of pancreatic epithelial cells to malignant pancreatic ductal adenocarcinoma (PDAC) typically involves the progression of precancerous pancreatic intraepithelial neoplasia (PanINs) bearing oncogenic KRAS mutations. Here, we tested the impact of PDAC interception using either RAS(ON) multiselective or RAS(ON) G12D-selective pharmacological inhibitors [RAS(ON) inhibitors] in mouse models of PDAC. Treatment of PanIN-bearing mice with RAS(ON) inhibitors prompted regression of premalignant lesions that translated into a delay in tumor onset and an increase in overall survival (OS). Long-term interception in tumor-prone mice resulted in a median OS of more than 1 year compared with less than 5 months in nonintercepted control mice (P < 0.0001). Comparing the survival benefits of RAS(ON) inhibition for cancer interception versus RAS(ON) inhibition for cancer treatment, we found that interception provided a greater survival benefit to mice. These findings suggest that a pharmacological approach may reduce premalignant burden and increase survival in PDAC.
    DOI:  https://doi.org/10.1126/science.aec7929
  2. bioRxiv. 2026 Mar 01. pii: 2026.02.27.708635. [Epub ahead of print]
    Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting.
    Yetiş Gültekin, Sharanya Sivanand, Kian M Eghbalian, Anna M Barbeau, Keene L Abbott, George Eng, Victoria L Tavernier, Brian T Do, Heaji Shin, Elif Özçelik, Sabrina Hu, Tenzin Kunchok, Millenia Waite, William M Rideout, Yiğit K Kizlier, Daniel A Sharygin, William A Freed-Pastor, Tyler Jacks, Eileen White, Ömer H Yilmaz, Jonathan A Nowak, Brian M Wolpin, Matthew G Vander Heiden.
      Normal pancreas function supports both digestion and the hormonal regulation of whole-body metabolism. We find pancreatic ductal adenocarcinoma (PDAC) disrupts the normal function of the remaining pancreas, leading to altered systemic metabolism and peripheral tissue wasting that begins early in disease progression. Using mouse models of PDAC, we find small pancreas tumors lead to both endocrine and exocrine pancreatic dysfunction that results in systemic nutrient depletion and loss of both muscle and fat tissue. Providing free glucose in the diet that is absorbed despite pancreatic exocrine dysfunction causes hyperglycemia and blunts fat wasting without affecting muscle loss. Muscle mass can be restored by free dietary amino acids or pancreatic enzyme supplementation. Exocrine dysfunction causing reduced dietary protein digestion promotes muscle proteolysis and autophagy. Autophagy is a major driver of muscle wasting in PDAC, as muscle-specific deletion of the core autophagy gene Atg7 also reduces muscle wasting. Disrupting muscle autophagy without restoring systemic nutrition slows tumor growth and improves survival of mice with PDAC. Tracing the fate of amino acids released from muscle of mice with PDAC shows redistribution to both tumor and host tissues. Notably, improving nutrition in mice with disrupted muscle autophagy promotes tumor growth. Together, the data argue that early peripheral tissue wasting associated with early pancreatic cancer is driven by altered normal pancreatic organ function that leads to reduced nutrition and enhanced muscle autophagy, releasing nutrients to support both tumor and host metabolism.
    DOI:  https://doi.org/10.64898/2026.02.27.708635
  3. Nat Cell Biol. 2026 Mar 13.
    Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
    Vera Skafar, Izadora de Souza, Biplab Ghosh, Ancely Ferreira Dos Santos, Florencio Porto Freitas, Zhiyi Chen, Shibo Sun, Merce Donate Castillo, Palina Nepachalovich, Lars Seufert, Sebastian Bothe, Juliane Tschuck, Apoorva Mathur, Ariane Nunes-Alves, Jannik Buhr, Camilo Aponte-Santamaría, Werner Schmitz, Matthias Mack, Martin Eilers, Ralf Bargou, Milena Chaufan, Mayher Kaur, Mario Palma, Jessalyn M Ubellacker, Ulrich Elling, Hellmut G Augustin, Kamyar Hadian, Svenja Meierjohann, Bettina Proneth, Marcus Conrad, Maria Fedorova, Hamed Alborzinia, José Pedro Friedmann Angeli.
      Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.
    DOI:  https://doi.org/10.1038/s41556-025-01856-x
  4. Cancer Discov. 2026 Mar 09. OF1
    Extracellular Matrix Sensing Controls Autophagy in Pancreatic Cancer.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-030
  5. Nat Struct Mol Biol. 2026 Mar 13.
    Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
    Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Colin J Delaney, Amr Al-Farhan, Alyssa J Mathiowetz, Cody E Doubravsky, Derek A Pratt, James A Olzmann.
      Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens using a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase and flavin adenine dinucleotide (FAD) synthase, enzymes that are essential for synthesizing FAD from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for both FSP1 activity and stability. FAD deficiency and mutations blocking FSP1-FAD binding triggered FSP1 degradation through a ubiquitin-proteasome pathway involving the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance, with implications for therapeutic strategies targeting FSP1 in cancer.
    DOI:  https://doi.org/10.1038/s41594-026-01759-x
  6. J Cell Biol. 2026 May 04. pii: e202509180. [Epub ahead of print]225(5):
    Mechanoresilience of lysosomes conferred by TMEM63A.
    Angelina S Kim, Jing Ze Wu, Ruiqi Cai, Spencer A Freeman.
      Lysosomes are subject to perturbations that can cause damage to their limiting membrane. Osmotic shifts, pore-forming toxins, and the growth of luminal polymers or pathogens all stand to increase lysosomal membrane tension and/or disrupt the bilayer. In some contexts, this leads to lysosomal rupture and cell death. Here, we describe a mechanism that enables lysosomes to sense and respond to acute increases in tension of their limiting membrane. We report that the lysosome-resident nonselective cation channel, TMEM63A, can drive the directional flux of monovalent cations, major osmoticants, out of the lumen when gated by mechanical tension on the organelle. This results in the ability for lysosomes to relieve hydrostatic pressure and, proportionally, membrane tension, affording lysosomes the time to acquire additional lipids. Lysosomes without this mechanism-either because TMEM63A is deleted or in the case when cells express disease-causing variants of TMEM63A-are an order of magnitude more sensitive to lysis upon increases to their membrane tension when compared with their WT counterparts. These findings suggest that lysosomes are capable of regulating hydrostatic pressure and volume in response to high tension.
    DOI:  https://doi.org/10.1083/jcb.202509180
  7. Nat Cell Biol. 2026 Mar 11.
    Fat bolsters tumours against ferroptosis.
    Eikan Mishima, Marcus Conrad.
      
    DOI:  https://doi.org/10.1038/s41556-026-01904-0
  8. Cancer Res. 2026 Mar 12.
    Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
    Chun-Hao Pan, Yinghuan Lyu, Monisankar Ghosh, Md Afjalus Siraj, Robert Tseng, Nina V Chaika, John D Haley, Bahman Khalvatifahlylani, David A Tuveson, Hardik D Patel, Muaz Faruque, Girish H Rajacharya, Katie L Donnelly, Cindy V Leiton, Carlos Mejia Arbelaez, Haoting Chen, Sumedha Chowdhury, Shayan Sarkar, Lyanne Delgado Coka, Lucia Roa-Peña, Michael Horowitz, Natalia Marchenko, Pankaj K Singh, Kenneth R Shroyer, Luisa F Escobar-Hoyos.
      The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is highly lethal and therapy resistant. A better understanding of the underlying molecular mechanisms driving this aggressive tumor subtype is necessary for the development of effective therapies. Notably, upregulation of keratin 17 (K17) in cancer is associated with poor patient outcome and the basal-like PDAC subtype. Here, we identified a critical dependency of basal-like PDACs on de novo pyrimidine biosynthesis, driven by intra-mitochondrial K17. Mechanistically, K17 translocated into the mitochondrial intermembrane space via a mitochondrial localization sequence (MLS) recognized by the translocase of the outer mitochondrial membrane 20 (TOM20). In the mitochondria, K17 bound to and stabilized dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of de novo pyrimidine biosynthesis, by preventing its ubiquitination-mediated degradation. Blocking the entry of K17 into the mitochondria sensitized cancer cells to gemcitabine, a pyrimidine analog and standard chemotherapeutic agent. In animal studies, pharmacologic inhibition of DHODH combined with gemcitabine treatment decreased tumor growth and doubled survival in mice bearing K17⁺ but not K17⁻ PDAC. These findings define a mitochondrial role for K17 in driving pyrimidine biosynthesis and uncover a metabolic vulnerability in K17⁺ basal-like PDACs that can be therapeutically targeted.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4534
  9. Langenbecks Arch Surg. 2026 Mar 09.
    Correlation between inflammation, vascularization, adipocyte percentage and exocrine cell percentage at the resection margin and the postoperative pancreatic fistula rate after distal pancreatectomy.
    Viola Palecek, Tutku Tüfekçi, Phillip Gärtner, Alexander Muckenhuber, Carsten Jäger, Rüdiger Göß, Ilaria Pergolini, Carmen Mota Reyes, Sergey Tokalov, Okan Safak, Mert Erkan, Helmut Friess, Rouzanna Istvanffy, Güralp Onur Ceyhan, Ihsan Ekin Demir, Elke Demir.
      
    Keywords:  Adipocytes; Exocrine cells; Fistula; Leukocytes; Macrophages; Pancreas; Stump; Surgery; Vascularization
    DOI:  https://doi.org/10.1007/s00423-026-04010-9
  10. Cancer Res. 2026 Mar 11.
    Inactivation of CDKN2AARF Promotes p53-Independent Remodeling of the PDAC Tumor Microenvironment.
    Sofia Ferreira, Brittany M Flowers, Won-Young Choi, Maria Farina-Morillas, Alberto Gatto, Sohinee Bhattacharyya, Gábor Boross, Ghmkin Hassan, Abigail S Mulligan, Hannes Vogel, Laura D Wood, Valerie M Weaver, Monte M Winslow, Dmitri A Petrov, Mara H Sherman, Hyo Young Choi, D Neil Hayes, Andrew J Aguirre, Jose A Seoane, Laura D Attardi.
      The CDKN2A locus, which is frequently deleted in pancreatic ductal adenocarcinoma (PDAC), encodes two tumor suppressors, ARF and INK4A, that may influence tumorigenesis through distinct mechanisms. Distinguishing their individual contributions to cancer could help improve the understanding of PDAC pathogenesis and potentially uncover targetable vulnerabilities. Moreover, while ARF is known to enhance p53 function, defining its p53-independent activities could elucidate processes that drive PDAC development. Here, we sought to understand ARF function in PDAC suppression. Expression and mutational patterns in human TCGA data indicated that CDKN2AARF and CDKN2AINK4A are commonly both affected by point mutations and/or deletions, suggesting that their combined inactivation contributes to PDAC development. In genetically engineered mouse models (GEMMs), Arf inactivation accelerated KRASG12D-driven PDAC development, both in the presence and absence of Trp53, demonstrating that ARF is a PDAC suppressor and can act in a p53-independent manner. Transcriptomic analyses of PDACs supported a p53-independent role for ARF, with ARF deficiency promoting extracellular matrix, collagen synthesis/assembly, and epithelial-mesenchymal transition gene expression programs. Accordingly, ARF-deficient PDACs displayed extensive remodeling of the tumor microenvironment (TME), associated with collagen deposition, increased tissue stiffness, and higher fibroblast content - hallmarks of aggressive and treatment-resistant PDAC stroma. Together, this study shows how ARF deficiency associated with CDKN2A inactivation sculpts the PDAC TME in a p53-independent fashion. Given the central role of the TME in PDAC progression and therapeutic resistance, these findings may provide insight critical for improving therapeutic interventions for PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1969
  11. Nat Cell Biol. 2026 Mar 13.
    Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer.
    Ming Liu, Anke Vandekeere, Xiao-Zheng Liu, Stephan Schenck, Juan Fernández-García, Tine Tricot, Yiming Peng-Winkler, Margherita Demicco, Dorien Broekaert, Ines Vermeire, Janine Theile, Gitte Zels, Anirudh Pabba, Christine Desmedt, Janine D Brunner, Patricia Altea-Manzano, Sarah-Maria Fendt.
      Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyltransferases and deacetylases is regulated remains often elusive. We focused on the lysine acetyltransferase 2A (KAT2A) as it is important in multiple cancer indications with a clinical inhibitor in development. We discovered that KAT2A expression is regulated by palmitoylation in breast cancer-derived metastases. Specifically, we find that the palmitoyltransferase DHHC20 (gene name ZDHHC20) palmitoylates transmembrane 4L six family member 1 (TM4SF1) promoting its plasma membrane localization. This in turn fosters phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which we identify as a transcriptional regulator of KAT2A. Accordingly, Zdhhc20 and Tm4sf1 silencing as well as expression of a Tm4sf1 double palmitoylation mutant decreases lung metastasis growth, which is rescued by Kat2a expression. We detect evidence of this palmitoylation-induced regulation of KAT2A in lung metastasis samples from patients with breast cancer. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases.
    DOI:  https://doi.org/10.1038/s41556-026-01913-z
  12. Nat Cell Biol. 2026 Mar 11.
    Peritumoural adipose tissue promotes ferroptosis resistance by 3-hydroxykynurenine-mediated suppression of ferritinophagy.
    Yan-Yu Zhang, Yi Han, Yue-Tao Tan, Yun-Xin Lu, Meng-Yao Ma, Yong-Qiang Zheng, Hao-Jie Chen, Hai-Yan Fu, Hai-Yu Mo, Qi-Nian Wu, Xiao-Jing Luo, Kun Liao, Wen-Qi Chen, Zhao-Lei Zeng, Hai-Long Piao, Hong-Li Du, Jun-Zhong Lin, Tian Tian, Rui-Hua Xu, Huai-Qiang Ju.
      The peritumoural adipose tissue (PAT) is a key contributor to cancer therapy resistance, yet its role in regulating ferroptosis remains unclear. Here we demonstrate that PAT confers ferroptosis resistance to cancer cells by upregulating ferritin (FTH1/FTL) and sequestering intracellular iron. PAT-derived kynurenine (KYN) was identified as the principal mediator. KYN is taken up by cancer cells and metabolized to 3-hydroxykynurenine, which directly binds to nuclear receptor coactivator 4 (NCOA4). This interaction inhibits NCOA4-mediated ferritinophagy, preventing ferritin degradation and limiting the free iron pool required for ferroptosis. In murine models, pharmacological inhibition of the KYN pathway synergized with PD-1 blockade to overcome ferroptosis resistance and suppress tumour progression. These findings reveal a PAT-KYN-ferritinophagy axis that promotes ferroptosis resistance, highlighting the potential of targeting adipose-tumour cross-talk to enhance immunotherapy in PAT-associated tumours.
    DOI:  https://doi.org/10.1038/s41556-026-01907-x
  13. Nature. 2026 Mar 11.
    Ageing promotes metastasis via activation of the integrated stress response.
    Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.
      Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-026-10216-0
  14. Autophagy. 2026 Mar 11. 1-18
    Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
    Mengqing Yang, Juan Chen, Xiang Su, Xianjin Kan, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Shengqing Yu, Chan Ding, Yingjie Sun.
      Lipid droplets (LDs) are dynamic organelles that store neutral lipids and maintain lipid homeostasis. Many viruses exploit LDs as replication platforms or lipid sources, but their role in supplying membrane lipids for viral assembly remains unclear. Newcastle disease virus (NDV), an enveloped RNA virus with oncolytic potential, extensively remodels host metabolism, yet its impact on LD lipid mobilization is unknown. Here, we show that NDV reprograms host lipid metabolism via SQSTM1/p62-dependent lipophagy, selectively degrading triglycerides (TAGs) enriched in unsaturated fatty acids (UFAs). Lipidomics revealed concurrent depletion of UFA-containing triglycerides (UFA-TAGs) and UFA-containing phosphatidylcholines (UFA-PCs) during infection. Inhibition of lipophagy blocked LD degradation, reduced viral replication, and suppressed UFA-PC formation. Isotope tracing demonstrated that lipophagy-derived UFAs are incorporated into phosphatidylcholines (PCs) via the Kennedy pathway, whereas β-oxidation was dispensable. UFA supplementation rescued viral replication under lipophagy blockade and promoted virus-like particle (VLP) release, indicating that UFA-PCs facilitate viral budding. These findings uncover a distinct NDV strategy linking lipophagy-driven UFA release to phospholipid synthesis and membrane remodeling, revealing a lipid-based metabolic vulnerability for antiviral and oncolytic interventions.Abbreviations: AP: autophagosome; ATG: autophagy related; ATP: adenosine triphosphate; CQ: chloroquine; EGFP: enhance green fluorescent protein; FFA: free fatty acid; HN: Hemagglutinin-Neuraminidase; LA: linoleic acid; LD: lipid droplet; LIPA: lipase A, lysosomal acid type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NDV: newcastle disease virus; NP: nucleoprotein; OA: oleic acid; PA: palmitic acid; PC: phosphatidylcholine; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; POA: palmitoleic acid; SFA: saturated fatty acid; TAG: triglyceride; UFA: unsaturated fatty acid; UFA-PC: UFA-containing phosphatidylcholine; VLP: virus-like particle.
    Keywords:  Newcastle disease virus; SQSTM1/p62; lipid droplets; lipophagy; phosphatidylcholine; unsaturated fatty acids
    DOI:  https://doi.org/10.1080/15548627.2026.2642980
  15. Biochem Soc Trans. 2026 Mar 25. pii: BST20250093. [Epub ahead of print]54(3):
    Breaking cellular boundaries: molecular mechanisms of tunneling nanotube formation and fusion.
    Sevan Belian, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) are thin, actin-based membrane bridges that establish direct cytoplasmic continuity between distant cells, enabling the transfer of diverse cargoes ranging from ions and proteins to organelles such as mitochondria. Since their discovery in 2004, TNTs have been identified in numerous cell types and linked to an expanding range of physiological and pathological functions. Yet, their molecular identity and mechanisms of formation remain elusive. The most defining and least understood step in TNT biogenesis is membrane fusion, the process by which TNTs achieve open-ended continuity between cells, and this represents a critical frontier in the field. This review integrates recent advances in TNT biology, emphasizing the interplay between actin cytoskeletal dynamics, plasma membrane composition, and cell adhesion during TNT formation. It also draws mechanistic parallels with established models of membrane fusion, highlighting fundamental principles and shared regulators across fusion systems, many of which have been implicated in TNT functionality. By combining molecular, biophysical, and imaging perspectives, this review proposes a conceptual framework for TNT formation and fusion, identifies major methodological gaps, and outlines future directions to unravel the mechanisms that underlie intercellular cytoplasmic continuity.
    Keywords:  Tunneling nanotubes; actin; cell homeostasis; cell-cell communication; membrane fusion
    DOI:  https://doi.org/10.1042/BST20250093
  16. Cancer. 2026 Mar 15. 132(6): e70343
    A randomized phase II trial of gemcitabine, nab-paclitaxel, cisplatin with or without a medically supervised ketogenic diet for patients with metastatic pancreatic cancer.
    Gayle S Jameson, Denise J Roe, Erkut Borazanci, Diana L Hanna, Caroline G P Roberts, Meredith S Pelster, Richard C Frank, Angela T Alistar, Alan M Miller, J Erin Wiedmeier-Nutor, Sandra D Algaze, Alison R Zoller, Sarah J Hallberg, Betsy C Wertheim, Keehoon Lee, Derek Cridebring, Joshua D Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Daniel D Von Hoff, Drew W Rasco.
       BACKGROUND: A randomized phase II screening trial of gemcitabine, nab-paclitaxel, and cisplatin with a medically supervised ketogenic diet (MSKD) versus usual diet (non-MSKD) was conducted in patients with treatment-naive metastatic pancreatic ductal adenocarcinoma (PDAC).
    METHODS: Patients with untreated metastatic PDAC were randomized 1:1 to MSKD or non-MSKD while receiving gemcitabine, nab-paclitaxel, and cisplatin on days 1 and 8 of a 21-day cycle. The MSKD was guided by a remote health care team and daily ketone (beta-hydroxybutyrate) levels, with goal beta-hydroxybutyrate of 0.5 to 3.0 mM. The primary endpoint was progression-free survival (PFS) using a one-sided alpha level of 0.20. Secondary endpoints included overall survival (OS), safety, and quality of life (QOL). Changes in microbiome were an exploratory endpoint.
    FINDINGS: Overall, there were 32 evaluable patients. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis; the median proportion of days in ketosis was 39.4%. The median PFS was 8.5 months in MSKD patients and 6.2 months in non-MSKD patients: hazard ratio, 0.53 (95% CI, 0.21-1.37); one-sided p = .096. The median OS was 13.7 months with MSKD and 10.2 months in the non-MSKD arm: hazard ratio, 0.58 (95% CI, 0.25-1.37); one-sided p = .107). All MSKD-related adverse events were grade 1-2. There were no significant differences in grade ≥3 chemotherapy-related adverse events between the arms. MSKD patients had no decline in QOL and had significant enrichment of beneficial taxa in the microbiome (p < .05, log-fold change ≥2).
    CONCLUSIONS: The MSKD is feasible in patients with PDAC and, although not powered for definitive outcomes, shows trends in improved PFS and OS when combined with gemcitabine, nab-paclitaxel, and cisplatin, without added toxicity or detriment to QOL. Larger studies are required to confirm these findings and establish the value of the MSKD in pancreatic cancer treatment.
    Keywords:  beta‐hydroxybutyrate; chemotherapy; ketogenic diet; microbiome; pancreas cancer
    DOI:  https://doi.org/10.1002/cncr.70343
  17. Trends Mol Med. 2026 Mar 12. pii: S1471-4914(26)00013-4. [Epub ahead of print]
    cAMP and mitochondrial dysfunction in cancer cachexia.
    Itamar C G Jesus, Julio C B Ferreira.
      A recent study by Angelino et al. uncovered an intracellular signaling pathway involved in musculoskeletal mitochondrial dysfunction in cancer cachexia. Both humans and mice with cancer cachexia display impaired 3',5'-cyclic adenosine monophosphate (cAMP)-protein kinase A-cAMP response element-binding protein 1 signaling, which leads to mitochondrial dysfunction. By rescuing this pathway with a phosphodiesterase-4 inhibitor, the authors highlight a potential therapeutic strategy for cancer cachexia.
    Keywords:  PDE4D; cAMP; cancer cachexia; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.molmed.2026.01.009
  18. Semin Cell Dev Biol. 2026 Mar 05. pii: S1084-9521(26)00006-6. [Epub ahead of print]179-180 103672
    Intra- and inter-organ communications in aging and cancer: Local and global spatial perspectives.
    Onkar Mulay, Aitor Benedicto, Yui Murata, Monica Suet Ying Ng, Jazmina L Gonzalez Cruz, Quan Nguyen.
      Interactions among neighbouring cells are fundamental to tissue function and can be specifically mapped using single-cell and spatial transcriptomics data. Overall, cell-cell interactions (CCIs) are essential for proper tissue function, including cell development, maintenance of tissue homeostasis, and immune responses during disease. Cells also communicate between organs by releasing signalling molecules into the circulatory system. We examined aging and cancer progression, the two important biological processes where alterations in CCIs remodel the tissue microenvironments that drive cellular and tissue dysfunction. Identifying these dysregulated interactions can uncover potential therapeutic strategies to prevent or treat disease by targeting specific ligand-receptor interactions. Interestingly, in aging and cancer metastasis, ligands originating from one organ can influence the aging processes of distant organs, while local interactions within the tumour microenvironment are critical for not only cancer dynamics at the primary site but also for driving its progression to secondary organs. This review highlights key ligand-receptor interactions in aging and cancer metastasis and examines intra- and inter-organ communication inference tools in this emerging field.
    Keywords:  Aging; Cancer; Cell-cell interactions; Inter-organ communication; Ligand-receptor; Metastasis
    DOI:  https://doi.org/10.1016/j.semcdb.2026.103672
  19. Sci Adv. 2026 Mar 13. 12(11): eaea1492
    Accelerated discovery of cell migration regulators using label-free deep learning-based automated tracking.
    Tiffany Chu, Yeongseo Lim, Yufei Sun, Fan Wu, Carolina Castillo, Eban Hanna, Denis Wirtz, Pei-Hsun Wu.
      Cell migration underlies immune surveillance, tissue repair, embryogenesis, and-when dysregulated-tumor metastasis. Yet unlike proliferation, which can be profiled at scale, migration studies remain limited by labor-intensive imaging and analysis. Existing assays often forfeit single-cell resolution, require phototoxic fluorescent labeling, or depend on tedious manual tracking, restricting the range of molecular perturbations and microenvironmental contexts that can be examined. We present Deep learning Brightfield Imaging and cell Tracking (DeepBIT), a high-throughput platform that captures live-cell behavior in multiwell plates and uses a convolutional neural network to detect and track individual cells in brightfield videos-without labels or user bias. Brightfield images are paired with nuclear fluorescence images to generate diverse ground-truth datasets, enabling automated training and eliminating manual annotation. This scalability supports a data-driven approach to systematically dissect the regulation of cell migration. Using breast cancer cells as a testbed, we tracked ~1500 cells per well across 840 conditions-including 96 FDA-approved drugs at multiple doses, a range of extracellular matrix and growth factor combinations, and CRISPR knockouts of cytoskeletal genes-yielding ~1.3 million trajectories in 30 hours (~2 minutes per condition). This dataset revealed previously unrecognized motility modulators among FDA-approved compounds and uncovered strong context dependence; for example, TNF-α and RhoA could either suppress or promote migration in the same cells depending on extracellular cues. Together, DeepBIT provides an unbiased, label-free platform for single-cell motility profiling at a scale compatible with modern drug libraries and genomic perturbation tools, enabling systematic exploration and therapeutic targeting of cell migration.
    DOI:  https://doi.org/10.1126/sciadv.aea1492
  20. STAR Protoc. 2026 Mar 10. pii: S2666-1667(26)00079-1. [Epub ahead of print]7(1): 104426
    Protocol to measure protein half-life in cell culture using heavy water.
    Lorena Alamillo, Alexander Black, Matthew C Juber, Dominic C M Ng, Maggie P Y Lam, Edward Lau.
      Protein turnover, comprising the continued synthesis and clearance of proteins, is required for protein homeostasis and cell survival. Here, we present a protocol to measure protein turnover half-life in cultured cells using D2O labeling. We describe steps to determine the extent of deuterium exchange in amino acids, perform dynamic labeling, and collect protein samples, followed by mass spectrometry and kinetic analysis. The protocol is suitable for measuring protein half-life under steady-state conditions and perturbations in multiple cell types and culture media. For complete details on the use and execution of this protocol, please refer to Alamillo et al.1.
    Keywords:  Cell culture; Mass Spectrometry; Protein Biochemistry; Proteomics; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2026.104426
  21. Elife. 2026 Mar 10. pii: RP108585. [Epub ahead of print]14
    Large-scale identification of plasma membrane repair proteins revealed spatiotemporal cellular responses to plasma membrane damage.
    Yuta Yamazaki, Keiko Kono.
      Damage to the plasma membrane (PM) is common in all types of cells. PM repair processes, including exocytosis and endocytosis, are not mutually exclusive; rather, they collaborate to repair the wound. However, the temporal coordination between the repair processes remains poorly understood. Here, by large-scale identification and live-cell imaging of PM repair proteins, we analyzed the spatiotemporal PM damage responses in Saccharomyces cerevisiae. Of the 80 repair proteins identified, 72 proteins were previously unreported repair protein candidates. Among the observed repair processes, the polarized exocytosis and clathrin-mediated endocytosis (CME) are coupled at the damage site, with exocytosis predominating in the early stage of PM repair and CME predominating in the late stage of PM repair. Furthermore, we showed that CME at the growing bud site directs PM repair proteins with transmembrane domains to the damage site. We propose a model in which CME delivers repair proteins with transmembrane domains between the growing bud site and the damage site. This study provides a functional catalog of PM repair proteins and insights into spatiotemporal cellular responses to PM damage.
    Keywords:  S. cerevisiae; budding yeast; cell biology; plasma membrane repair; visual screening
    DOI:  https://doi.org/10.7554/eLife.108585
  22. Nutrients. 2026 Mar 05. pii: 837. [Epub ahead of print]18(5):
    Impact of Vitamin D Status on Pancreatic Cancer Risk and Outcomes.
    Beata Jabłońska, Sławomir Mrowiec.
      Vitamin D (VD), a fat-soluble prohormone, exerts diverse effects on cellular proliferation, differentiation, and immune modulation, with accumulating evidence supporting its role in pancreatic ductal adenocarcinoma (PDAC) biology. Experimental studies demonstrate that VD and its analogs can inhibit PDAC cell growth and remodel the tumor microenvironment, potentially contributing to tumor suppression. Epidemiological data indicate that VD deficiency is prevalent among PDAC patients and is associated with increased inflammatory biomarkers and reduced overall survival, particularly in early-stage disease. However, meta-analyses reveal inconsistent associations between circulating 25-hydroxyvitamin D levels and PDAC incidence, while higher levels may be linked to improved survival but not reduced risk of disease onset. The clinical utility of VD supplementation for PDAC prevention or treatment remains uncertain, with ongoing debate regarding optimal dosing, timing, and patient selection. This narrative review synthesizes current evidence on the mechanistic, epidemiological, and clinical relevance of VD in PDAC. Particular emphasis is placed on existing knowledge gaps and the need for well-designed clinical trials to clarify the potential therapeutic and prognostic role of VD in pancreatic cancer.
    Keywords:  calcitriol; pancreatic cancer; pancreatic ductal adenocarcinoma; tumor microenvironment; vitamin D
    DOI:  https://doi.org/10.3390/nu18050837
  23. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2514484123
    Adhesion forces between macrophages and cancer cells promote early tumor development.
    Jovan Nikolic, Joseph Ackermann, Ines Marin, Sarah Taheraly, Morgane Mabire, François-Xavier Gobert, Mathieu Maurin, Apolline de Testas de Folmont, Ouardia Aït-Mohamed, Edison Gerena, Sophie Goyard, Jérémy Mesple, Hélène Salmon, Thierry Rose, Christine Moussion, Martine Ben Amar, Jean-François Joanny, Philippe Benaroch.
      Biochemical mechanisms of macrophage-driven tumor promotion are well documented, but the contribution of physical forces to early tumor development remains poorly understood. Here, we combine experimental analyses with physical modeling to investigate these forces in KrasG12D p53-/- (KP) lung tumor spheroids grown in 3D. Real-time microscopy showed that tissue-resident macrophages, but not monocytes, promote early tumor growth. Using quantitative measurements, we built a physical model that recapitulates cancer cell proliferation dynamics and macrophage-tumor interactions. KP tumor cells grown alone formed a single aggregate that contracted over time due to nutrient limitation, whereas macrophages induced the formation of multiple aggregates that grew, fused, and expanded nutrient access, thereby increasing proliferation. Similar macrophage-driven growth was observed when alveolar or bone-marrow-derived macrophages were cocultured with KP or pancreatic carcinoma cells. The model predicted a redistribution of macrophages toward the periphery of aggregates, a pattern confirmed in vitro and previously observed in vivo. It also identified adhesion forces between tumor cells and macrophages as a key driver of spheroid nucleation and growth. Among candidate integrins, CD11c was highly expressed by alveolar macrophages; CD11c blockade reduced adhesion forces, prevented macrophage-driven spheroid nucleation, and impaired tumor growth. Bone-marrow-derived macrophages required simultaneous CD11b and CD11c blockade for similar effects. Finally, CD11c inhibition in RAG-Knock Out (KO) mice reduced tumor survival probability and slowed the growth of ear-implanted tumors, indicating that CD11c-dependent interactions support tumor establishment beyond the lung. Together, these findings uncover a critical physical mechanism through which macrophages promote early tumor progression.
    Keywords:  macrophage; physical forces; tumor
    DOI:  https://doi.org/10.1073/pnas.2514484123
  24. Clin Cancer Res. 2026 Mar 09.
    Overcoming adaptive resistance to KRASG12D blockade in pancreatic cancer through vertical pathway inhibition.
    Qingxiang Lin, Alvin A Morales-Giron, Conrad Sander, Jacquelyn M Curtis, Haley Barnes, Parasvi S Patel, Ferran Fece de la Cruz, Jakob M Riedl, Hiroyuki Matsubara, Hajime Nakamura, Andrew S Liss, Ryan B Corcoran.
       PURPOSE: Oncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC) with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, where EGFR-mediated RAS-MAPK pathway reactivation can be targeted toimprove response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear.
    EXPERIMENTAL DESIGN: Mechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models.
    RESULTS: We observed RTK-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models, but limited to those with epithelial differentiation. Conversely, adaptive RAS MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from TCGA, EGFR and ERBB3 expression was highly correlated with expression of epithelial markers, while expression of FGFR1 and mesenchymal markers were correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared to combinations of KRASi and EGFR blockade.
    CONCLUSIONS: In PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in PDAC patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1788
  25. Int J Mol Sci. 2026 Mar 02. pii: 2342. [Epub ahead of print]27(5):
    The Roles of SQSTM1/p62 in Selective Autophagy and Oncogenic Signaling.
    Young-Jun Kim, Hwa-Hyeong Lee, Tae Young Jung, Young-Hoon Jeong, Key-Hwan Lim, Ji Min Han.
      Autophagy is a critical cellular mechanism that regulates the degradation of misfolded and aggregated proteins and non-functional intracellular organelles. Based on the fundamental qualities of the substrates targeted for degradation and the distinct molecular mechanisms involved, autophagy can be classified into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Sequestosome 1 (SQSTM1)/p62, which functions as a signaling hub integrating nuclear factor kappa B (NF-κB), the mechanistic target of rapamycin complex 1 (mTORC1), and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathways, serves as a selective macroautophagy/autophagy receptor that binds ubiquitinated cargo proteins and recruits them to the autophagosome for subsequent degradation in the autolysosome. Furthermore, the phase separation of p62 is an important regulatory process in the autophagy mechanism, but recent studies have demonstrated that impaired or excessive autophagy mediated by p62 is associated with cancer development. This review summarizes the role of autophagy-including its types, mechanisms, and the pathway related to the ubiquitin-dependent selective autophagy receptor p62-in cancer progression.
    Keywords:  autophagy; cancer; oncogene; p62; ubiquitin
    DOI:  https://doi.org/10.3390/ijms27052342
  26. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70237
    Downregulation of Organ-Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice.
    Cui Wang, Lin Gao, Rui Xue, Jia Su, Honghui Li, Wei Yang, Yan Tang, Zhihang Su, Shasha Min, Changyong Tang, Yuqi Zhu, Bo Mu, John R Speakman, Xina Xie, Zesong Li.
       BACKGROUND: Cancer cachexia is a multifactorial wasting syndrome marked by profound skeletal muscle loss. Tumours can release high levels of Activin A (ActA), which activates the ubiquitin-proteasome pathway (UPP) and drives muscle wasting. Systemic blockade of the ActA pathway is associated with inflammatory adverse effects, and tumour-restricted targeting alone often fails to reverse cachexia. We asked whether ActA produced by host (nontumour) organs contributes to circulating ActA and muscle wasting.
    METHODS: We profiled ActA across tissues and in serum in Lewis lung carcinoma (LLC) cancer cachexia mice to generate an organ-wide expression map. Functional studies were then performed using adeno-associated-virus (AAV)-knockdown in the heart (cTnT/hTCF21 promoters) and kidney (CMV promoter), followed by cachexia induction. Body weight (BW), food intake, skeletal muscle mass, muscle function and muscle histomorphology were assessed. Mitochondrial ultrastructure and lipid metabolic pathways in muscle and adipose tissue were also examined.
    RESULTS: LLC cachexia mice exhibited significant reductions in body weight (-6.0%, p < 0.05), food intake (-9.9%, p < 0.05), quadriceps mass (-15.3%, p < 0.05) and grip strength (-13.0%, p < 0.0001) compared with non-tumour-bearing (NTB) mice (n = 6-12/group). ActA expression was markedly increased in the host organs, particularly in the kidney (2.8-fold vs. NTB, p < 0.001) and heart (2.7-fold vs. NTB, p < 0.05) (n = 10/group). Compared with the sh-NC, organ-targeted ActA knockdown restored body weight (+6.1%, p < 0.05) and food intake (+8.4%, p < 0.05), increased quadriceps mass (+17.2%, p < 0.05) and grip strength (+10.7%, p < 0.01), reduced intramuscular fat infiltration and attenuated UPP signalling (n = 8-16/group). These effects were accompanied by increased expression of the mitochondrial fatty-acid oxidation regulator carnitine palmitoyltransferase 1B (CPT1B) (+42.3% of mRNA level; +30.9% of protein level; both p < 0.05) and CPT2 (+57.7% of mRNA level, p < 0.05), improved mitochondrial ultrastructure and partial restoration of adipose mass.
    CONCLUSIONS: Simultaneous downregulation of Activin A in the kidney and heart attenuates skeletal muscle atrophy and intramuscular adipogenesis, improves muscle mass and function and mitigates adipose tissue mass loss in cancer cachexia mice. These findings identify heart- and kidney-derived Activin A as a key driver of cachexia, which acts through a combinatorial effect rather than an isolated contribution from either one alone, highlighting its potential as a therapeutic target.
    Keywords:  Activin A; cancer cachexia; heart and kidney; intramuscular fat infiltration; muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.70237
  27. Sci Signal. 2026 Mar 10. 19(928): eaeg1158
    AI might be the next stage of our natural evolution: A cancer neuroscience perspective.
    Ihsan Ekin Demir, Carmen Mota Reyes, Maximilian Berlet, Elke Demir, Ibrahim Halil Gürcinar, Güralp O Ceyhan, Helmut Friess, Rouzanna Istvanffy, Dirk Felix Wilhelm.
      Cancer neuroscience is an emerging field at the intersection of oncology, neuroscience, and immunology in which the interactions between cancer cells and neural and immune systems generate extraordinary biological complexity. Thus, artificial intelligence may be a technological tool that is increasingly necessary to decode nonlinear cancer-neuron networks and to translate this complexity into biological and therapeutic insight.
    DOI:  https://doi.org/10.1126/scisignal.aeg1158
  28. Physiol Rev. 2026 Mar 12.
    The Lethal Symbiont: Exploring the Pathophysiology of Cancer.
    Emma Nolan, Leanne Li, Evangelos Giampazolias, Luigi Ombrato, Ilaria Malanchi.
      From its early genesis, cancer is integrated with the surrounding tissue. Its very existence depends on surrounding normal tissue cells engaging with cancer cells to create an alternative tissue environment. This emerging abnormal structure becomes connected with the host organism via blood, lymphatic vessels, and neural connections. Through those connections, the cancer mass communicates and perturbs the entire organism altering various aspects of the steady state body physiology. At early, asymptomatic stages, the induced changes within distant organs that harbour the potential to facilitate the spread of cancer are termed "premetastatic niche". Many processes involved with pre-metastatic changes hijack processes typical in other context such as development, injury, or infections, but their co-occurrence creates a new alternative physiology. The cancer to body connections not only have important consequences for the efficacy of cancer therapy but enable cancer to evolve and adapt under the very pressure of those treatments. Furthermore, as cancer induced changes are closely related to other physiological challenges, extrinsic perturbations such as diet, injury, and other inflammatory events, have strong impact on the tumour disease. As the disease progresses, the complex intersection of inflammatory, metabolic, regenerative changes creates an escalating cascade of events causing cancer related syndrome, such as cachexia, that threaten the homeostasis of the entire body and can, per se, be deadly. In this article we will review the recent advances in the understanding of cancer as systemic malady.
    DOI:  https://doi.org/10.1152/physrev.00019.2025
  29. Science. 2026 Mar 12. 391(6790): 1104-1105
    KRAShing pancreatic cancer before takeoff.
    Benjamin G Neel, Anirban Maitra.
      Drugs that inhibit KRAS signaling delay the development of pancreatic cancer in mice.
    DOI:  https://doi.org/10.1126/science.aef6665
  30. Nat Cell Biol. 2026 Mar 13.
    Time-resolved functional genomics using deep learning reveals global hierarchical control of autophagy.
    Nathalia Chica, Aram N Andersen, Sara Orellana-Muñoz, Ignacio Garcia, Aurélie Nguéa P, Sigve Nakken, Pilar Ayuda-Durán, Linda Håkensbakken, Sebastian W Schultz, Eline Rødningen, Christopher D Putnam, Manuela Zucknick, Tor Erik Rusten, Jorrit M Enserink.
      Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remains limited, particularly regarding how autophagy is inactivated once nutrients are restored. Here we mapped the genetic network that controls activation and inactivation of autophagy during nitrogen changes by combining time-resolved high-content imaging, deep learning and latent feature analysis. This dataset, termed AutoDRY, categorizes 5,919 mutants based on nutrient response kinetics and their contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data uncovered hierarchical and multilayered control of autophagy and revealed multiple new regulatory pathways. Notably, we identified the retrograde pathway as a pivotal time-varying modulator that tunes the expression of core autophagy genes and plays a central role in autophagy inactivation. Together, this study establishes a systems-level resource to guide future investigations of autophagy.
    DOI:  https://doi.org/10.1038/s41556-025-01837-0
  31. Nat Cell Biol. 2026 Mar 09.
    TOLLIP targets GSDME-NT-carrying endocytic vesicles for autophagy to regulate pyroptosis and chemotherapy efficacy.
    Zhimin Xu, Zhe Li, Zhenji Deng, Cong Ding, Jiawei Wu, Chuqing Zhang, Hanmiao Wei, Tingxiang He, Liufen Long, Linglong Tang, Jun Ma, Xiaoyu Liang.
      Whether pyroptosis is controllable and reversible remains an enigma. Here we revealed that autophagy could eliminate the pore-formed N terminus of GSDME (GSDME-NT) located on membranes at different locations, suppressing pyroptosis. Crucially, GSDME-NT on the plasma membrane was eliminated through endocytic internalization, where GSDME-NT-laden vesicles were targeted and degraded as intact units. Specifically, GSDME-NT pores on the plasma membrane induced endocytosis, generating endocytosed but leaky vesicles carrying GSDME-NT. Leakage prevented acidification, necessitating further degradation through autophagy. Upon endocytosis, GSDME-NT on the vesicle membrane was labelled with ubiquitin by calcium-activated E3 ligase NEDD4L. These labelled vesicles were recognized by TOLLIP, guiding subsequent autophagosome formation, and enabling further acidification, fusion with lysosomes and eventual GSDME-NT degradation. Furthermore, in several tumour models, either disturbing autophagy or interfering with the recognition of GSDME-NT vesicles by targeting TOLLIP increased tumour cell pyroptosis, activating antitumour immunity and promoting chemotherapeutic efficacy.
    DOI:  https://doi.org/10.1038/s41556-026-01902-2
  32. Cancer Metastasis Rev. 2026 Mar 12. pii: 14. [Epub ahead of print]45(1):
    Early cellular plasticity promotes progression and dissemination in pancreatic adenocarcinoma.
    Giulio Innamorati, Giorgio Malpeli, Luca Giacomello, Roberto Salvia, Thomas M Wilkie.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic success and a persistently low 5-year survival rate. Despite significant advances in genomics and tumor biology, a fundamental challenge persists: to identify the elusive transformation from common benign pancreatic lesions to occasional malignant cellular identity. This review addresses a critical missing link in PDAC pathogenesis, focusing on when and where the switch to malignancy occurs, and why surgical intervention is often insufficient. We explore the biological and spatial-temporal evolution of precancerous lesions, such as PanINs and IPMNs, and examine how phenotypic plasticity and overlapping cellular programs-including squamous transdifferentiation, epithelial-to-mesenchymal transition (EMT), and acquisition of mesenchymal features-contribute to early dissemination, treatment resistance, and surgical failure. Recognizing and characterizing these early molecular events is essential for rethinking therapeutic strategies, identifying actionable biomarkers, and redefining the temporal window when curative intervention is feasible.
    Keywords:  Cellular plasticity; Early cancer dissemination; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1007/s10555-026-10326-1
  33. Science. 2026 Mar 12. 391(6790): eaec1778
    Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer.
    Corleone S Delaveris, Rita P Loudermilk, Apurva Pandey, Soumya G Remesh, Trenton M Peters-Clarke, Snehal D Ganjave, William J N Dougherty, Henry M Delavan, Chunyue Wang, Jesse Ling, Juan Antonio Camara Serrano, Fernando Salangsang, Chien-Kuang Cornelia Ding, Nancy Greenland, Carissa E Chu, Sima Porten, Veronica Steri, Jonathan Chou, Michael J Evans, Kevin K Leung, James A Wells.
      Overexpression of the proto-oncogene Src is common to a wide variety of cancers. In this work, we found that Src is noncanonically translocated and inverted onto the cell surface in cancer, both in vitro and in vivo. We identified autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines. Src represents the prototypical example of a family of membrane-anchored proteins that are transported by this process. Furthermore, this extracellular membrane-associated Src (eSrc) was found in primary tumors, and anti-Src antibody-based therapies mediated tumor cell killing in cell culture systems and in mouse xenograft models. Thus, intracellular N-myristoylated proteins, prototypically Src, can be topologically inverted onto the cell surface in cancer and targeted with antibody therapeutics.
    DOI:  https://doi.org/10.1126/science.aec1778
  34. STAR Protoc. 2026 Mar 11. pii: S2666-1667(26)00078-X. [Epub ahead of print]7(1): 104425
    Protocol for immunofluorescence detection and quantitative analysis of pH-dependent transcriptional condensates.
    Zhongyang Wu, Krishnan Raghunathan, Zhe Zhong, Jay Thiagarajah, Xu Zhou.
      Acidic pH regulates the assembly of transcriptional condensates containing BRD4 and MED1 in a variety of mouse and human cells. Here, we present a protocol to image and quantify BRD4 condensates in bone marrow-derived macrophages. We describe steps for preparing macrophage growth medium at controlled pH levels, performing immunofluorescence experiments, and acquiring images with Airyscan confocal and STED super-resolution microscopy. We detail image processing pipelines to analyze condensate properties using FIJI, CellProfiler, and a custom MATLAB program. For complete details on the use and execution of this protocol, please refer to Wu et al.1.
    Keywords:  Cell culture; Immunology; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2026.104425
  35. Int J Cancer. 2026 Mar 07.
    Arp2/3 complex and β1 integrin drive an invasive front through extracellular matrix adaptation in pancreatic cancer.
    Xiufen Yang, Yina Qiao, Yifeng Sun, Tamer Abdelaal, Kathleen Schuck, Hend Abdelrasoul, Carolina De La Torre, Malte Hermes, Yan Dong, Jingxiong Hu, Chao Fang, Xiaoyan Huang, Christoph Kahlert, Ingrid Herr, Christoph W Michalski, Bo Kong.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, due to its aggressive invasiveness and resistance to therapy. The dense, stiff extracellular matrix, composed primarily of collagen I and basement membrane components such as collagen IV and laminin, acts as a mechanical barrier that constrains PDAC invasion. We investigated whether the actin-related protein (Arp) 2/3 complex, a key actin nucleator, is essential for PDAC cells to overcome extracellular matrix stiffness and facilitate migration. CRISPR/Cas9 knockout of the Arpc4 gene in murine PDAC cell lines derived from KrasG12D-driven transgenic mice resulted in substantially downregulated all Arp2/3 complex members. Inactivation of Arp2/3 significantly impaired PDAC cell migration, disrupted branched tubular structure formation in collagen I, and inhibited invasive front formation in organoid culture together with tumor-associated macrophages and fibroblasts. Mechanistically, β1 integrin signaling emerged as a key regulator of Arp2/3-dependent migration through collagen-rich matrices. Clinically, elevated expression of Arp2/3 complex components correlates with poor patient survival and basal-like differentiation subtypes, underscoring its role in disease progression. This study identifies the Arp2/3 complex and β1 integrin signaling as critical mediators of PDAC invasiveness and suggests them as potential therapeutic targets for mitigating PDAC progression.
    Keywords:  Arp2/3; extracellular matrix; integrin; pancreatic cancer; type I collagen
    DOI:  https://doi.org/10.1002/ijc.70376
  36. Bioinformatics. 2026 Mar 12. pii: btag122. [Epub ahead of print]
    Scalable analysis of whole slide spatial proteomics with Harpy.
    Benjamin Rombaut, Arne Defauw, Frank Vernaillen, Julien Mortier, Evelien Van Hamme, Sofie Van Gassen, Ruth Seurinck, Yvan Saeys.
       MOTIVATION: Current spatial proteomics data analysis workflows are limited in efficiency and scalability when applied to gigapixel sized datasets. Moreover, they often lack extensive quality control tools and exhibit limited interoperability with existing spatial omics analysis ecosystems.
    RESULTS: We introduce Harpy, a new Python workflow capable of accelerated processing of large spatial proteomics datasets. We demonstrate the utility of Harpy on four datasets and show that it can rapidly apply state-of-the-art segmentation and feature extraction via parallel processing. Each analysis step is accompanied by appropriate quality control steps. Scalable clustering of cells and pixels allows identification of cell types, processed up to 27 times faster than previously reported. Processing and visualization can be performed locally or on high-performance computing servers. Additionally, Harpy integrates well with existing spatial single-cell analysis tools in the Python and R software ecosystem.
    AVAILABILITY AND IMPLEMENTATION: Harpy is available on GitHub at https://github.com/saeyslab/harpy and archived on Zenodo at https://doi.org/10.5281/zenodo.15546703.
    SUPPLEMENTARY INFORMATION: Supplementary data are available online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag122
  37. Anal Chem. 2026 Mar 10.
    Systematic and Quantitative Investigation of Newly Synthesized Proteins Reveals Distinct Ion Homeostasis and Mitochondrial Changes between Cuproptosis and Ferroptosis in Human Cells.
    Yue Wu, Longping Fu, Xing Xu, Pak San Chan, Ronghu Wu.
      Dysregulated metal ion metabolism and its connection to cell death attract great attention in cell biology and biomedicine. There are two major types of known metal ion-induced cell death so far. Well-documented ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation, and the recently discovered cuproptosis is copper-dependent cell death, possibly related to mitochondrial damage and cell stress. Although some studies have suggested a possible link between cuproptosis and ferroptosis, the cellular responses and mechanistic differences between these two forms of metal ion-dependent cell death remain to be explored. Here, we systematically and quantitatively analyzed newly synthesized proteins (NSPs), which reflect rapid changes in gene expression, in cells undergoing ferroptosis and cuproptosis through integrating metabolic labeling, bioorthogonal chemistry, and multiplexed proteomics. The results revealed that both types of cell death shared some common features, such as mitochondrial disorder and gene expression suppression. Furthermore, different changes between them were also uncovered. In cuproptosis, proteins related to zinc ion homeostasis were elevated because intracellular copper and zinc ions are cooperatively and competitively involved in multiple biological processes, and excess copper ions impact zinc ion homeostasis in cells. Moreover, damaged mitochondria were found to be cleared mainly through ubiquitin-mediated mitophagy. In contrast, ferroptosis is associated with an increased level of calcium-binding proteins and a compensatory upregulation of key antioxidant defense systems while concurrently showing a notable decrease in RNA alternative splicing-related proteins. Taken together, a comprehensive and comparative analysis of NSPs in cuproptosis and ferroptosis provides us with a unique opportunity to understand the molecular mechanisms of these two important forms of metal ion-dependent cell death.
    DOI:  https://doi.org/10.1021/acs.analchem.5c07257
  38. Angew Chem Int Ed Engl. 2026 Mar 13. e26137
    Wash-Free Multi-Target Super-Resolution Microscopy With Photocaged DNA Labels.
    Nina Kaltenschnee, Marina S Dietz, Laurell F Kessler, Yunqing Li, Janik Kaufmann, Alexander Heckel, Mike Heilemann.
      Super-resolution microscopy with DNA-fluorophore labels is primed for multi-target imaging of cell biological samples. However, direct interaction with the sample is required to exchange or add DNA-fluorophore labels in each imaging round, which can impair the accuracy of the imaging data at the nanometer scale. To bypass this requirement, we introduce PhotoPAINT, a wash-free method that employs DNA oligonucleotides equipped with photocaging groups. Irradiation with light removes these photo-modulatable groups and changes the hybridization properties of DNA labels, enabling light-modulated targeting. We demonstrate this concept by imaging various cellular targets with confocal microscopy, single-molecule localization microscopy (SMLM), and stimulated emission depletion (STED) microscopy.
    Keywords:  DNA‐PAINT; light control; multiplexed imaging; photocages; single‐molecule localization microscopy
    DOI:  https://doi.org/10.1002/anie.202526137
  39. Nat Methods. 2026 Mar;23(3): 486
    Bringing magnetofluorescent proteins into the cell.
    Fariha Rahman.
      
    DOI:  https://doi.org/10.1038/s41592-026-03040-x
  40. Commun Med (Lond). 2026 Mar 11.
    Multilevel metabolic adaptation to exercise training.
    Tzachi Knaan, Eylam Ziv-Av, Gal Dubnov-Raz, Irit Markus, David Peled, Paulee Manich, Daniel Barazany, Maayan Ramati, Gal Aziel, Chen Luxenburg, Carmit Levy, Edward L Melanson, Yftach Gepner.
       BACKGROUND: Exercise training often produces less weight loss than expected, a phenomenon termed exercise-induced energy compensation, but the underlying mechanisms remain unclear. This study aimed to quantify metabolic and behavioral compensation to aerobic exercise training.
    METHODS: Sixteen sedentary adults with overweight completed a 12-week supervised aerobic walking intervention targeting an energy expenditure of 20 kcal/kg/week. Total daily energy expenditure was measured using doubly labeled water, and whole-room calorimetry was used to assess changes in resting and sleeping metabolic rate (RMR, SMR) and diet-induced thermogenesis (DIT). Volumes of highly metabolic organs were quantified by magnetic resonance imaging. Physical activity was monitored objectively, walking economy was assessed during standardized treadmill walking, and dietary intake was evaluated using self-report and intake-balance methods. A parallel mouse exercise model was used to explore tissue-level adaptations.
    RESULTS: Exercise training induces substantial energy compensation, resulting in minimal body weight loss despite improved body composition. Total daily energy expenditure increases, while RMR and SMR decrease, accounting for most of the compensatory response. Liver and kidney volumes decrease by 5%, while brain volume remains unchanged. Exercise improves walking economy and leads to smaller-than-expected increases in daily moderate-to-vigorous physical activity. Dietary intake and DIT remain unchanged. In mice, exercise is associated with increased cellular density and mitochondrial content in the liver, indicating structural and metabolic remodeling.
    CONCLUSIONS: Aerobic exercise training engages compensatory physiological and behavioral mechanisms that constrain energy expenditure. Reductions in basal metabolism, improved movement efficiency, and selective remodeling of metabolically active organs may collectively limit exercise-induced weight loss.
    DOI:  https://doi.org/10.1038/s43856-026-01502-z
  41. Nano Lett. 2026 Mar 13.
    Assembly Module-Empowering Lipid-Prodrug Nanoamplifier for Enhancing Ferroptosis-Driven Cancer Treatment.
    Xinxin Sun, Dongqi Sun, Zehua Wu, Jin Sun, Cong Luo, Zhonggui He, Shenwu Zhang.
      Ferroptosis has been widely explored as a promising cancer therapeutic target. Conventional ferroptosis induction relies on inhibiting glutathione peroxidase 4 (GPX4) to promote lipid peroxide accumulation. However, its efficacy is often limited by insufficient endogenous unsaturated lipids in tumor cells. To address this limitation, we developed a lipid-prodrug nanoamplifier (SIM-SS-LA NAs), composed of disulfide-linked linoleic alcohol and simvastatin (SIM) to enhance ferroptosis. Significant, the modularity of the prodrug not only promotes the assembly of the SIM but also amplifies its ferroptosis effect. In the highly reductive tumor microenvironment, disulfide bonds are cleaved, releasing SIM and LA. Notably, the released LA acts as an exogenous substrate, substantially increasing lipid peroxide accumulation and synergizing with SIM-mediated GPX4 inhibition to amplify ferroptosis. As expected, the lipid-prodrug nanoamplifier showed potent ferroptosis-driven antitumor activity in a 4T1 breast tumor-bearing mouse model, offering an efficient nanotherapeutic strategy for ferroptosis-based cancer therapy.
    Keywords:  Ferroptosis; Glutathione peroxidase 4; Lipid peroxidation; Lipid-prodrug; Nanoamplifier
    DOI:  https://doi.org/10.1021/acs.nanolett.6c00154
  42. Trends Mol Med. 2026 Mar 12. pii: S1471-4914(26)00012-2. [Epub ahead of print]
    Decoding GPX4 regulation in ferroptosis: mechanisms and therapeutic implications.
    Xin Chen.
      Ferroptosis, a regulated form of cell death, is determined by iron-dependent lipid peroxidation. A selenoenzyme called glutathione peroxidase 4 (GPX4) detoxifies phospholipid hydroperoxides at the heart of this process. As the pivotal gatekeeper of ferroptosis, GPX4 is implicated in a wide range of pathologies, including cancer, neurodegeneration, acute renal failure, and infection. In this review, we discuss how GPX4 transcription and mRNA stability are controlled by transcription factors, epigenetic modifications, and noncoding RNAs and how GPX4 degradation and activity are modulated by post-translational modifications, including ubiquitination, phosphorylation, palmitoylation, methylation, hydroxylation, and lactylation. We also summarize new therapeutic methods targeting GPX4, namely the ferroptosis inducers for cancer therapy and ferroptosis inhibitors that prevent ferroptosis-related damage.
    Keywords:  GPX4; autophagy; ferroptosis; modification; proteasome; transcription
    DOI:  https://doi.org/10.1016/j.molmed.2026.01.008
  43. Biol Cell. 2026 Mar;118(3): e70056
    Healing Wounds.
    A Harrouet, L Anger, M Hautefeuille, M A Fardin.
      Wound healing has long provided a framework for studying cell and tissue dynamics, yet early contributions are often overlooked. Revisiting research from the late 19th to mid-20th centuries reveals enduring questions on migration versus proliferation, individual versus collective motion, and chemical versus mechanical drivers. Concepts such as contractility, collective motility, and contact inhibition illustrate the continuity of debate across generations. By reconnecting these foundational studies with modern advances, we highlight persistent gaps and offer historical context to guide future research.
    DOI:  https://doi.org/10.1111/boc.70056
  44. Sci Data. 2026 Mar 12.
    STHELAR, a multi-tissue dataset linking spatial transcriptomics and histology for cell type annotation.
    Félicie Giraud-Sauveur, Quentin Blampey, Hakim Benkirane, Arianna Marinello, Paul-Henry Cournède, Stergios Christodoulidis.
      Understanding the composition of the tumor microenvironment is critical for cancer research. Spatial transcriptomics profiles gene expressions in spatial context, revealing tissue architecture and cellular heterogeneity, but its cost and technical complexity limit adoption. To address this issue, we introduce a pipeline to build STHELAR, a large-scale dataset that integrates spatial transcriptomics with Hematoxylin and Eosin (H&E) whole-slide images for cell type annotation. The dataset comprises 31 human Xenium FFPE sections across 16 tissue types, for 22 cancerous and 9 non-cancerous patients. It contains over 11 million unique biological cells, each assigned to one of ten curated cell-type categories designed to accommodate a pan-cancer setting. Annotations were derived through Tangram-based alignment to single-cell reference atlases, followed by slide-specific clustering and differential expression analysis. Co-registered H&E images enabled the extraction of over 500,000 patches with segmentation and classification masks. Quality control steps assessed segmentation accuracy, filtered out low-confidence regions, and verified annotation integrity. STHELAR provides a reference resource for developing models to predict cell-type annotations directly from histological images.
    DOI:  https://doi.org/10.1038/s41597-026-06937-6
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