bims-cagime 2026-04-26 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–04–26
39 papers selected by
Kıvanç Görgülü, Technical University of Munich

Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.
Separating food intake-dependent and -independent effects in cancer cachexia.
Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.
Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
AI-powered Deep Visual Proteomics reveals critical molecular transitions in pancreatic cancer precursors.
Heterogeneity and plasticity of cancer-associated fibroblasts.
Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.
Piezo1-mediated mechanohydraulic control of cell volume drives cardiac morphogenesis.
Dietary Fat Content Influences PanIN Progression and Pancreatic Cancer Development in Mice.
Ferroptosis surveillance: Insights from in vivo contexts.
OSBPL10 Drives Lipophagy-Mediated Lipid Mobilization to Promote Pancreatic Ductal Adenocarcinoma Progression.
A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.
A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.
The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.
Cell-free chromatin epigenomic profiling enables non-invasive pancreatic cancer cell-state identification.
The sleeping threat: targeting cancer dormancy to transform metastasis therapy.
Inhibition of Focal Adhesion Restricts Chemoresistance in Pancreatic Cancer by Targeting SLC7A11 Mediated Ferroptosis.
The ubiquitin ligase RNF115 is required for the clearance of damaged lysosomes.
Development and Release of the Munich UICC Staging Tool (MUST): Advancing UICC Staging in Real-World Data With Insights From Pancreatic and Stomach Cancer.
Synthetic mechanobiology.
Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma.
Senescent cell heterogeneity: origins, detection, and therapeutic implications.
An autochthonous CRISPR activation screening platform for characterizing tissue-specific oncogene selection.
High-quality acinar cell isolation enables single-cell analysis of healthy and injured pancreas.
Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.
The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.
Prolonged KRAS-MAPK Inhibition Induces Interferon Signaling that Promotes Cell State Transition and Confers Therapeutic Vulnerabilities.
Homeostatic pressure of a proliferating multicellular foam with hydromechanical volume regulation.
Histological fidelity and microenvironmental kinome signatures of metastatic patient-derived organoids.
A pressure relief valve for lysosomes.
Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.
Proteomic characterization of primary pancreatic fibroblasts derived from neoadjuvant chemotherapy treated versus treatment-naïve PDAC.
A lipid-centric view of endocytosis by caveolae.
Cell shapes decode molecular phenotypes in image-based spatial proteomics.
ASO-based PKM splice-switching therapy increases anti-CTLA-4 antibody efficacy in pancreatic ductal adenocarcinoma.
Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity.
Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer.
Mimicking nature: Models of lipid membranes created with the Langmuir monolayer technique: A review of lipid membrane composition.

FEBS J. 2026 Apr 24.

Lipid droplet biogenesis as a metabolic switch regulating ferroptosis sensitivity in cancer cells.

Abdulsamie Hanano, Amal Yousfan.

  Fatty acids (FAs) are essential for cellular growth and homeostasis; however, their excessive accumulation induces lipotoxicity. To prevent FA-induced damage, eukaryotic cells sequester surplus FAs within cytosolic lipid droplets (LDs), dynamic organelles central to lipid storage, metabolism, and signaling. Emerging evidence indicates that LDs suppress ferroptosis, an iron-dependent programmed cell death, by channeling polyunsaturated fatty acids (PUFAs) away from membrane phospholipids, thereby limiting lipid peroxidation. Nonetheless, the molecular mechanisms linking LD biogenesis to ferroptosis susceptibility remain poorly defined. In a recent study published in The FEBS Journal, Kump et al., provided mechanistic insights into how triacylglycerol (TGs) biosynthesis and LD assembly regulate ferroptosis in cancer cells as a function of PUFA availability. Here, we discuss and contextualize their principal findings.

Keywords:  Acyl‐CoA diacylglycerol acyltransferase; ferroptosis; lipid droplets; lipid peroxidation; polyunsaturated fatty acids

DOI:  https://doi.org/10.1111/febs.70567
iScience. 2026 May 15. 29(5): 115525

Separating food intake-dependent and -independent effects in cancer cachexia.

Yanshan Liang, Young-Yon Kwon, Sheng Hui.

  Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle, with diminished food intake commonly cited as a cause. However, the extent to which reduced food intake drives these symptoms, and other phenotypes such as physical weakness, remains unclear. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and tissue wasting, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing weakness. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.

Keywords:  Cancer; Nutrition; Physiology

DOI:  https://doi.org/10.1016/j.isci.2026.115525
Nat Cell Biol. 2026 Apr 24.

Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.

Mariantonietta D'Ambrosio, Matthew E H White, Efthymios S Gavriil, Laura Bousset, Jodie Birch, Aleksandra Gruevska, Emiliano Pasquini, Manuel Colucci, Winnie Fong, Simone Mosole, Aurora Valdata, Dimitris Veroutis, Katie Tyson, Vikas Ranvir, Sandra Prokosch, Joaquim Pombo, Aoki Ardisson, Sanjay Khadayate, George Young, Alex Montoya, Georgia Roumelioti, Jack Houghton, Jianan Lu, Pavel V Shliaha, Elena De Vita, Santiago Vernia, Vassilis G Gorgoulis, Suchira Gallage, Mathias Heikenwälder, Zoe Hall, Andrea Alimonti, Iain A McNeish, Edward W Tate, Jesús Gil.

Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.

DOI: https://doi.org/10.1038/s41556-026-01921-z
Cancer Res. 2026 Apr 21.

Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.

Mitchell E Fane, Daniel J Zabransky.

Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-1612
Cancer Discov. 2026 Apr 21.

AI-powered Deep Visual Proteomics reveals critical molecular transitions in pancreatic cancer precursors.

Jimin Min, Lisa Schweizer, Gijs Zonderland, Benson Chellakkan Selvanesan, Julie H Thomsen, Lukas Oldenburg, Seong-Woo Bae, Bongjun Kim, Sharia D Hernandez, Gabriela Jez, Vincent Bernard, Benjamin J Swanson, Kelsey A Klute, Huamin Wang, Thomas C Caffrey, Paul M Grandgenett, Michael A Hollingsworth, Ishani Ummat, Maximilian T Strauss, Andreas Mund, Anirban Maitra.

Pancreatic ductal adenocarcinoma (PDAC) evolves through precursors, yet the protein programs governing early progression remain poorly defined. We applied Deep Visual Proteomics - integrating computational pathology, laser microdissection, and mass spectrometry - to profile normal ducts, acinar-to-ductal metaplasia (ADM), low- and high-grade pancreatic intraepithelial neoplasia (PanIN), and invasive carcinoma from organ donors and patients with PDAC. Quantifying 9,181 proteins from ~100 cells per region, we uncovered a molecular field effect in histologically normal ducts and proteomic divergence of low-grade PanINs by cancer context. We identified four stage-associated molecular programs. Stress adaptation and immune engagement emerged early in cancer-associated normal ducts. Metabolic reprogramming initiated in normal ducts and intensified across PanIN progression. Mitochondrial remodeling became prominent in high-grade PanINs before invasion. Mass spectrometry detected KRAS hotspot mutant peptides within incidental precursor lesions from cancer-free individuals. These findings demonstrate that molecular reprogramming precedes histological transformation, creating opportunities for earlier detection of lethal cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1119
Nat Cancer. 2026 Apr 20.

Heterogeneity and plasticity of cancer-associated fibroblasts.

Sneha Pramod, Hagar Lavon, Ruth Scherz-Shouval, Mara H Sherman.

Fibroblasts sense and respond to contextual cues to support tissue structure and function. In cancer, they engage a dysregulated wound-healing response that profoundly shapes tumor composition and progression. Efforts to therapeutically target these cancer-associated fibroblasts (CAFs) have been complicated by their heterogeneity and plasticity. However, recent advances, particularly in single-cell and spatial technologies, have greatly improved the understanding of the phenotypic consequences of distinct CAF states and functions. Here we review the current understanding of CAFs as heterogeneous, instructive regulators of tumor microenvironments across anatomic sites and highlight key challenges for the future.

DOI: https://doi.org/10.1038/s43018-026-01146-x
FEBS Lett. 2026 Apr 19.

Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.

Shiho Machii, Kazushi Morimoto, Pakawit Lerksaipheng, Mirinthorn Jutanom, Ken-Ichi Yamada.

  Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα-PDK4-PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence-ferroptosis interaction.

Keywords:  PDH; PDK4; PPARα; cellular senescence; cystine deprivation; ferroptosis; mitochondrial function

DOI:  https://doi.org/10.1002/1873-3468.70332
Sci Adv. 2026 Apr 24. 12(17): eaea7025

Piezo1-mediated mechanohydraulic control of cell volume drives cardiac morphogenesis.

Christina Vagena-Pantoula, Konstantinos Kalyviotis, Shuyi Feng, Antoine Sanchez, Igor Kondrychyn, Moe Fukumoto, Xiangbin Pan, Thomas Juan, Didier Y R Stainier, Periklis Pantazis, Li-Kun Phng, Julien Vermot.

Organ morphogenesis is driven by physical forces, yet how mechanical stimuli pattern tissue shape and guide developmental programs remains poorly understood. In zebrafish, endocardial cells (EdCs) within the heart valve-forming region undergo marked volume reduction during early morphogenesis. Here, we uncover a hydraulics-based mechanism by which mechanical forces control EdC volume to direct cardiac development. We show that the mechanosensitive ion channel Piezo1 acts with the calcium-binding protein calmodulin (CaM) and the aquaporin Aqp8a.1 water channel to orchestrate EdC shrinkage. We find that Aqp8a.1 mediates cell volume loss by incorporating into the plasma membrane in response to mechanical stimulation, promoting heart looping and valve formation. Mechanistically, Piezo1 governs Aqp8a.1 through a dual mechanism. First, Piezo1 and CaM drive Aqp8a.1 plasma membrane incorporation, enabling rapid cell volume adjustments. Second, Piezo1 suppresses aqp8a.1 transcription via Notch1b signaling to prevent excessive shrinkage. Together, these findings reveal that mechanotransduction can dictate organ formation through dynamic cell volume regulation, uncovering a fundamental principle of morphogenesis.

DOI: https://doi.org/10.1126/sciadv.aea7025
Cancer Res Commun. 2026 Apr 19.

Dietary Fat Content Influences PanIN Progression and Pancreatic Cancer Development in Mice.

Urvinder Kaur Sardarni, Erika Y Faraoni, Alyssa M Waller, Lincoln N Strickland, Baylee O'Brien, Kelsey A Klute, Jesse L Cox, Florencia McAllister, Jennifer M Bailey-Lundberg.

Dietary macronutrient composition has emerged as a key modulator of pancreatic tumorigenesis, yet the impact of lipid-rich diets, particularly ketogenic diets (KD) on the earliest stages of pancreatic cancer development remains unclear. To investigate how dietary lipids shape the initiation and progression of Kras-driven neoplasia, we examined the effects of low-fat diet (LFD), high-fat diet (HFD), and KD in the Ptf1aCreERT2;KrasG12V (AcinarKrasG12V) mouse model. KD-fed mice showed the shortest survival (median 26 ± 7 days) compared with standard diet (SD, 87 ± 29; p = 0.02) and LFD (57 ± 27; p = 0.02), while HFD-fed mice also exhibited reduced survival relative to SD (35 ± 25; p = 0.05). KD feeding was associated with severe glucose intolerance and elevated circulating β-hydroxybutyrate levels. Histologically, KD-fed AcinarKrasG12V mice developed invasive, sarcomatoid-like PDAC, while HFD-fed mice showed increased poorly differentiated PDAC; in both groups these aggressive tumors were associated with extensive fibrosis and increased stromal CD39 expression relative to tumor compartments. Proteomic analysis demonstrated activation of PI3K-Akt-mTOR and EGFR signaling pathways in tumors from KD and HFD-fed AcinarKrasG12V mice. Serum cytokines/chemokines profiling revealed pro-inflammatory and pro-angiogenic milieu in KD-fed AcinarKrasG12V mice. Collectively, these results suggest that dietary lipid enrichment prior to oncogenic Kras activation is associated with accelerated early pancreatic neoplasia and a microenvironment conducive to tumor progression. These findings underscore the need for careful consideration of KD use in individuals at elevated risk for pancreatic cancer.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0777
Ferroptosis Oxid Stress. 2026 ;pii: 202523. [Epub ahead of print]2(3):

Ferroptosis surveillance: Insights from in vivo contexts.

Alec J Vaughan, Mario Palma, Jessalyn M Ubellacker, Thales Papagiannakopoulos.

  Ferroptosis has emerged over the past decade as a compelling therapeutic avenue for cancer, prompting intense interest in strategies that selectively induce or inhibit this form of cell death. Although substantial progress has been made in identifying genes that regulate ferroptosis sensitivity and in developing small-molecule modulators, it remains unclear which molecular targets offer the greatest therapeutic potential in specific tissues and contexts. Here, we highlight fundamental differences between in vitro and in vivo ferroptosis modulation, with emphasis on the integration of different techniques, mouse models, and how the tumor microenvironment shapes two major ferroptosis surveillance pathways: glutathione peroxidase 4 and ferroptosis suppressor protein 1. We propose that integrating in vivo biological constraints and microenvironmental complexity is essential for the rational design and successful translation of ferroptosis-targeted therapies.

Keywords:  Ferroptosis; GPX4–FSP1 axis; in vivo modeling; microenvironment

DOI:  https://doi.org/10.70401/fos.2026.0021
Int J Biol Sci. 2026 ;22(7): 3769-3787

OSBPL10 Drives Lipophagy-Mediated Lipid Mobilization to Promote Pancreatic Ductal Adenocarcinoma Progression.

Zonghao Duan, Xueshiyu Ma, Feng Yu, Junfeng Zhang, Rong Hua, Wei Liu, Dejun Liu, Jianyu Yang, Xueliang Fu, Minwei Yang, Hongfei Yao, Shuheng Jiang, Lipeng Hu, Musitaba Mutailifu, Xiaomei Yang, Yongwei Sun, Linli Yao, Yanmiao Huo.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, in which the role of lipophagy, a selective autophagic process degrading lipid droplets (LDs), remains poorly characterized. This study investigated lipophagy and its key regulator, OSBPL10, in PDAC progression. Through immunofluorescence analysis of patient samples, transgenic mouse tissues, and cell lines, we find that lipophagy is elevated in PDAC and correlates with poor prognosis. Single-cell transcriptomic analysis identified OSBPL10 as a critical lipophagy regulator and an independent clinicopathological indicator. Functional assays, including orthotopic and subcutaneous xenografts, demonstrated that OSBPL10 promotes tumor growth. Mechanistically, OSBPL10 functionally cooperates with VAPA/VAPB to facilitate rapid lysosomal repair via ATG2A, thereby promoting lipophagy and lipid mobilization. Inhibition of lysosomal function abrogated the pro-lipophagic and pro-tumorigenic effects of OSBPL10. Collectively, our findings demonstrate that upregulated OSBPL10 drives PDAC progression by enhancing lipophagy through ATG2A-mediated rapid lysosomal repair, highlighting OSBPL10 as a potential therapeutic target in PDAC.

Keywords:  PDAC; autophagy; lipid metabolism; lipophagy; rapid lysosomal repair

DOI:  https://doi.org/10.7150/ijbs.125552
Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770

A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.

Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.

  Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.

Keywords:  PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.xcrm.2026.102770
Cancer Discov. 2026 Apr 20. OF1-OF20

LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.

Ray Pillai, Ali Rashidfarrokhi, Yuan Hao, Warren L Wu, Mariana C S Mancini, Burcu Karadal-Ferrena, Sofia G Dimitriadoy, Michael Cross, Anna H Yeaton, Shih Ming Huang, Arjun Bhutkar, Alberto M Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-Lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Ellie Ivanova, Corrin Wohlhieter, Sarah E LeBoeuf, Ting Chen, Cynthia A Loomis, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw Aleksander Smolen, Jun-Chieh J Tsay, Fernando Moreira Simabuco, Charles M Rudin, Andre L Moreira, Kamal M Khanna, Harvey I Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B Koralov, Thales Papagiannakopoulos.

LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression.
SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0470
Dev Cell. 2026 Apr 21. pii: S1534-5807(26)00122-X. [Epub ahead of print]

A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.

Silvia Campanario, Mercedes Grima-Terrén, Megan Rommelfanger, Stefania Dell' Orso, Xuesong Feng, Andrés Cisneros, Ignacio Ramírez-Pardo, Aina Calls-Cobos, Benjamin A Yang, Kyung Dae Ko, Esther García-Domínguez, Laura Pena-Couso, Grace Chou, Yuewen Zheng, Nasun Hah, Davide Randazzo, Alberto Pérez-Garcia, Tovah E Markowitz, Jose Milisenda, Iago Pinal-Fernandez, Andrew Mammen, Mari Carmen Gómez-Cabrera, Antonio L Serrano, Eusebio Perdiguero, Vittorio Sartorelli, Joan Isern, Pura Muñoz-Cánoves.

  The molecular basis underlying muscle atrophy, as it occurs during disuse or aging, and activity-induced hypertrophy remain poorly understood. A major challenge has been defining the diverse cellular and niche environments within skeletal muscle, which is mostly composed of multinucleated myofibers. Here, we present a single-nucleus and single-cell transcriptomic atlas, coupled with spatial profiling, of mouse limb skeletal muscle under resting conditions and during experimentally induced atrophy or hypertrophy. We identify condition-dependent shifts in muscle-resident cell populations and fiber-type-specific transcriptional responses. We also uncover extensive remodeling of the neuromuscular junction (NMJ), including the emergence of specialized synaptic myonuclei (SynM) and terminal Schwann cells (tSCs) associated with atrophic or hypertrophic states. High-resolution 3D imaging and spatial transcriptomics confirm these changes at the tissue level. Similar NMJ alterations are observed in denervated and exercised human muscle, supporting the translational relevance of this atlas for studying muscle plasticity and identifying therapeutic targets in muscle-related diseases.

Keywords:  Schwann cell; atrophy; cell atlas; hypertrophy; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1016/j.devcel.2026.03.010
Toxicol Res. 2026 May;42(3): 325-343

The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.

Eun-Ji Choi, Sang-Min Jeon.

  Sequestosome 1 (SQSTM1/p62), long established as a selective autophagy receptor and ubiquitin-binding scaffold, is now recognized as an emerging regulatory hub that integrates signaling, metabolism, and stress adaptation in cancer. Beyond its canonical role in proteostatic cargo degradation, recent advances have revealed that p62 orchestrates nutrient sensing, redox control, innate immune signaling, and metabolic reprogramming through highly dynamic, context-dependent mechanisms. A nascent paradigm emerging from recent studies is that p62 function is specified by a hierarchical post-translational modification (PTM) code, with phosphorylation acting as the primary regulatory layer. Site-specific phosphorylation events-together with modulatory PTMs such as S-acylation, arginine methylation, and O-GlcNAcylation-reshape p62 interaction networks, liquid-liquid phase separation (LLPS) behavior, and signaling output. Through these mechanisms, p62 operates as a sophisticated signal-metabolism interface that couples stress signaling pathways, including NFE2L2/NRF2, AMPK, mTORC1, and NF-κB to the systemic rewiring of glucose, lipid, amino acid, and nucleotide metabolism. Notably, a phosphorylation-dependent positive feedback loop between p62 and AMPK has emerged as a key driver of metabolic plasticity, enabling tumor cells to survive and proliferate under the stringent metabolic stress conditions of the tumor microenvironment. This review integrates recent mechanistic insights into the PTMs, phase behavior, and signaling hub functions of p62, highlighting how these principles manifest in distinct oncogenic contexts, such as lung, prostate, and brain tumors. We further discuss emerging therapeutic strategies that seek to modulate p62-centered assemblies rather than indiscriminately inhibit p62 function. Collectively, these findings position p62 as a phosphorylation-governed oncogenic nexus whose precise manipulation may enable new strategies for context-dependent precision oncology.

Keywords:  AMPK; Cancer; Metabolism; NFE2L2/NRF2; SQSTM1/P62; Signaling

DOI:  https://doi.org/10.1007/s43188-026-00349-9
medRxiv. 2026 Apr 06. pii: 2026.04.02.26349987. [Epub ahead of print]

Cell-free chromatin epigenomic profiling enables non-invasive pancreatic cancer cell-state identification.

Karl Semaan, Marc Eid, Damien Vasseur, Gunsagar S Gulati, Cibelle Lima, Elio Ibrahim, Ji-Heui Seo, John J Canniff, Hunter Savignano, Alexander Jordan, Leigh Culnane, Noa Phillips, Rashad Nawfal, Aislyn Schalck, Andressa Dias Costa, Elizabeth A Andrews, Emma C Coleman, Talal El Zarif, Garyoung Gary Lee, Razane El Hajj Chehade, Ze Zhang, Gaelle Nafeh, Wassim Daoud Khatoun, Brady James, Zhenjie Jin, Paulo Da Silva Cordeiro, Brad Fortunato, David Peng, Christopher Vellano, Tim Heffernan, Antoine Hollebecque, Antoine Italiano, Brandon M Huffman, James M Cleary, Jacob E Berchuck, Toni K Choueiri, Kimberly J Perez, Jonathan Nowak, Andrew J Aguirre, Brian M Wolpin, Sylvan C Baca, Matthew L Freedman, Harshabad Singh.

Classical and basal-like transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) are prognostic and may predict response to different chemotherapy regimens and RAS inhibitors. Current subtyping methods rely on tissue biopsies and remain challenging to integrate into clinical workflows. Herein, we present a novel approach for non-invasive subtyping of PDAC based on epigenomic profiling of circulating tumor DNA (ctDNA). In a multi-omics cohort of patient-derived xenografts, we identify highly recurrent regulatory elements associated with classical and basal-like PDAC. We then demonstrate that these epigenomic signatures can identify PDAC subtype from plasma epigenomic profiling in a multi-institutional cohort of patients with metastatic PDAC and integrate information from circulating histone modifications and DNA methylation to develop the Pancreatic Integrated Epigenomic Score (PIES). PIES is concordant with tissue-based labels and captures transcriptional subtype heterogeneity observed within biopsies. Furthermore, it improves prognostication over tissue-based subtyping suggestive of the recovery of ground truth tumor biology from plasma ctDNA. Our work provides a proof-of-concept for a circulating biomarker that enables transcriptional subtyping and informs therapeutic decisions in pancreatic cancer.
Significance: Transcriptional subtyping of pancreatic cancer can improve prognostication and inform treatment selection. Current subtyping approaches rely on tissue biopsy, are challenging to implement in clinical practice, and are limited by tumor heterogeneity and sampling error. Herein, we introduce a cell-free DNA-based epigenomic assay capable of inferring pancreatic cancer subtypes noninvasively.

DOI: https://doi.org/10.64898/2026.04.02.26349987
Nat Rev Cancer. 2026 Apr 24.

The sleeping threat: targeting cancer dormancy to transform metastasis therapy.

Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero, Wenjun Guo, Gregoire Lauvau, Maria Soledad Sosa.

Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.

DOI: https://doi.org/10.1038/s41568-026-00928-w
Adv Sci (Weinh). 2026 Apr 20. e75216

Inhibition of Focal Adhesion Restricts Chemoresistance in Pancreatic Cancer by Targeting SLC7A11 Mediated Ferroptosis.

Yingjin Wang, Hui Yang, Baoyuan Zhang, Yongsu Ma, Kuangen Zhang, Peng Wang, Jiapeng Yang, Zaiqi Wang, Rong Liu, Xiaodong Tian, Ning Zhang, Yinmo Yang.

  Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) is common and complex, accompanied with chemotherapy process. Gemcitabine-based chemotherapy regimens have shown limited antitumor effects for PDAC, and combination targets are urgently needed to restrict chemoresistance. We attempted to identify the candidate targets with gemcitabine (Gem) through scRNA-seq and bulk-seq analysis based on chemotherapy-treated and Gem-resistant (GR) samples, respectively. The mechanisms were investigated with experimental validation in vitro and in vivo preclinical PDAC models. We found that chemoresistance and evolution after chemotherapy of PDAC were associated with activation of focal adhesion signal. Mechanistically, the focal adhesion kinase (FAK) inhibitor (IN10018) could restrict chemoresistance to Gem of PDAC by targeting SLC7A11-mediated ferroptosis through PI3K-Akt signaling pathway. For tumor microenvironment, IN10018 reduced the abundance of mesenchymal components and enhanced CD8+ T cell infiltration.

Keywords:  chemoresistance; ferroptosis; focal adhesion kinase; pancreatic cancer; scRNA‐seq

DOI:  https://doi.org/10.1002/advs.75216
FEBS Lett. 2026 Apr 24.

The ubiquitin ligase RNF115 is required for the clearance of damaged lysosomes.

Sae Nakanaga, Toshiki Takahashi, Akiko Kuma, Hiroyuki Kawahara.

  Lysosomes play a critical role in the quality control of cellular organelles. However, lysosomal membranes can be damaged under a variety of conditions, leading to the onset of various diseases. Damaged lysosomes are selectively cleared via a ubiquitin-dependent mechanism, but the molecular mechanisms underlying this process have not been adequately elucidated. In this study, we found that RNF115 is a lysosomal damage-responsive ubiquitin ligase that undergoes massive translocation from the cytosol to the p62/SQSTM1-positive puncta around ruptured lysosomes. In accordance with the changes in its distribution, the depletion of RNF115 delayed the removal of Gal3 from damaged lysosomes during the restoration process following lysosomal damage. These observations suggest that RNF115 is responsible for the clearance of damaged lysosomes.

Keywords:  BAG6; E3 ubiquitin ligase; RNF115; autophagy; lysophagy; lysosomal membrane damage; lysosome

DOI:  https://doi.org/10.1002/1873-3468.70346
Int J Cancer. 2026 Apr 18.

Development and Release of the Munich UICC Staging Tool (MUST): Advancing UICC Staging in Real-World Data With Insights From Pancreatic and Stomach Cancer.

Brigitte Kühnel, Sophie Schneiderbauer, Sebastian Lange, Dirk Wilhelm, Helmut Friess, Marcus Feith, Ursula Ehmer, Florian Bassermann, Julian W Holch, Stefan M Munker, Jens Neumann, Jens Werner, Hubert J Stein, Theres Fey, Ulrich Mansmann, Hana Algül, Karin Berger-Thürmel, H Carlo Maurer, Daniel Nasseh.

  Accurate cancer staging is essential for cancer research and treatment evaluation; however, real-world data (RWD) often include incomplete or inconsistent UICC classifications. We present the development, optimization, demonstration, and release of the Munich UICC Staging Tool (MUST), an open-source R script that automates UICC staging based on TNM classifications and tumor characteristics, improving data completeness and consistency. MUST incorporates official UICC staging rules (6th-8th editions). A key feature is the application of RWD-specific rules to handle missing values and incomplete information. The tool is transparent, highly customizable, and adaptable to future TNM versions and diverse applications. MUST was validated using anonymized clinical tumor registry data from two Munich university hospitals (analyzed independently, n > 100,000), focusing on pancreatic and stomach cancers. Compared to documented UICC stages, MUST increased staging completeness from 60% to 72% in Clinic-1 and from 20% to 74% in Clinc-2. Agreement rates between documented and MUST-generated UICC stages were 90% in Clinic-1 and 95% in Clinic-2. To assess reliability, a Confidence Level metric summarizes the proportion of original versus additional rules applied. 70% of MUST-derived stages in Clinic-1 and 48% in Clinic-2 were classified as "Assured," with the remaining cases relying on RWD-specific rules. The results demonstrate that RWD-specific rules substantially improve completeness, while the differences between clinics highlight variations in documentation and coding practices. MUST offers a reliable solution for UICC staging, addressing documentation gaps and improving data quality. Its adaptability makes it valuable for clinical documentation, registries, and large-scale oncology studies.

Keywords:  MUST tool; TNM classification; UICC staging; cancer informatics; real‐world data

DOI:  https://doi.org/10.1002/ijc.70488
Curr Biol. 2026 Apr 20. pii: S0960-9822(26)00292-7. [Epub ahead of print]36(8): R309-R317

Synthetic mechanobiology.

John T Ngo.

Cells do not simply endure mechanical forces - they generate, transmit, and interpret them as biological signals. From membrane tension and receptor pulling to substrate stiffness and fluid shear, physical inputs shape migration, differentiation, immune function, and tissue organization. Whereas mechanobiology seeks to understand how living systems read these cues, synthetic mechanobiology treats mechanoregulatory pathways as an input-output relationship that can be deliberately programmed. Integrating tools from synthetic biology with mechanobiological principles, this emerging field reframes force-sensing as a design problem in which mechanical signaling is rewired to achieve useful outcomes - and in which the act of rewiring can itself serve as a powerful investigational strategy. Here, I survey the molecular mechanisms of mechanosensing, describe their use as modular mechanogenetic parts, and discuss applications and open challenges. The long-term vision is to build engineered cells that not only read tissue mechanics but act on them, turning the physical signatures of disease into precise, locally delivered therapeutic programs.

DOI: https://doi.org/10.1016/j.cub.2026.03.005
Cancer Cell. 2026 Apr 23. pii: S1535-6108(26)00174-1. [Epub ahead of print]

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma.

Rodrigo Entrialgo-Cadierno, Konstantina Morali, Iker Feliu, Yingyun Wang, James W Evans, Mariana Yañez-Bartolome, Ines Lopez, Irati Macaya, Cristina Cueto-Ureña, Daniel Sin-Coscujuela, Yaiza Senent, Jose M Herranz, Rashi Raghulan, Javier Vaquero, Jesus M Banales, Teresa Macarulla, Mariano Ponz-Sarvise, Ximo Pechuan-Jorge, Elisabeth Guruceaga, Alyssa Schumpp, Alia V Garcia, Alyssa Kim, Benjamin O Herzberg, Nilofer Azad, Aparna Hegde, Tian V Tian, Ida Aronchik, Mallika Singh, Jingjing Jiang, Silve Vicent.

  About 25% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.

Keywords:  KRAS oncogene; RAS(ON) multi-selective inhibitor; biliary tract cancer; cholangiocarcinoma; drug combinations; preclinical models; targeted therapy; therapy resistance

DOI:  https://doi.org/10.1016/j.ccell.2026.03.020
Trends Cell Biol. 2026 Apr 18. pii: S0962-8924(26)00058-9. [Epub ahead of print]

Senescent cell heterogeneity: origins, detection, and therapeutic implications.

Rong Wu, Junyu Zhu, Hayoon Kim, Ming Xu.

  Although senescent cells are commonly characterized by stable cell cycle arrest, emerging evidence indicates that senescence is not a uniform state but a collection of highly heterogeneous phenotypes. This heterogeneity stems from biological factors, such as diverse senescence markers, cellular origins, and targeting mechanisms, as well as from technical variations in experimental approaches, notably in the design of transgenic mouse models. By summarizing recent advances in next-generation senolytic strategies, multiomics profiling, and genetically engineered mouse models of senescence, we provide an integrated perspective on the origins and consequences of senescent cell heterogeneity. Such a perspective is essential for refining investigative methodologies and for developing precise therapies that selectively target senescent cell populations whose roles have been experimentally validated in vivo.

Keywords:  aging; p16; p21; senescence; senolytics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.tcb.2026.03.015
Cell Rep Med. 2026 Apr 17. pii: S2666-3791(26)00176-X. [Epub ahead of print] 102759

An autochthonous CRISPR activation screening platform for characterizing tissue-specific oncogene selection.

Fredrik I Thege, Amber Hoskins, Annaliese Kramer, Intisar Salim, Ashwath Seetharaman, Natalie Fowlkes, Kimal I Rajapakshe, Anirban Maitra, Sonja M Wörmann.

  Human adenocarcinomas exhibit tissue-specific mutation and copy-number patterns that suggest diverse selective pressures and distinct oncogene dependencies. Here, we use our FiCASCan platform to test whether in vivo CRISPR activation screening can recapitulate oncogene selection during tumor initiation. Using CRISPRa-competent PPKS mice and intranasal or intraductal delivery of pooled lentivirus, we screen frequently amplified and mutated genes in autochthonous lung and pancreas cancer models. We observe strong selection for Egfr, Myc, Sox2, and Pik3cb activation in lung tumors and near-complete dominance of Myc in pancreatic tumors, revealing striking tissue-specific differences. In our model, Sox2 activation suppresses Nkx2-1 signaling and drives aggressive mucinous lung adenocarcinoma. MYC activation in the pancreas mirrors MYC amplification in human PDAC, including the emergence of an immune-cold microenvironment. Overall, our findings show that in vivo CRISPR activation screening faithfully captures oncogene selection and provides a powerful approach for studying tumor initiation and progression.

Keywords:  LUAD; MYC; PDAC; and SOX2; human adenocarcinoma; in vivo CRISPR activation screening; oncogenes; tumorigenesis

DOI:  https://doi.org/10.1016/j.xcrm.2026.102759
Cell Rep Methods. 2026 Apr 20. pii: S2667-2375(26)00115-3. [Epub ahead of print] 101415

High-quality acinar cell isolation enables single-cell analysis of healthy and injured pancreas.

Nirav Florian Chhabra, Leeanne J Mundle, Henrik Einwächter, Roland M Schmid.

  Acinar cells are the predominant cell type of the pancreas. However, in single-cell RNA sequencing datasets from healthy murine pancreas, acinar cells typically represent less than half of the total cells. Here, we developed a protocol that facilitates the rapid digestion of the pancreas into high-quality single cells from both healthy and caerulein-induced acute pancreatitis (AP) tissue. Under homeostatic conditions, acinar cells exhibited limited heterogeneity, with distinct subpopulations selectively and highly expressing protease genes or transcription factors, mirroring patterns observed in the healthy human pancreas. Moreover, 24 h after AP, acinar cells displayed heterogeneous expression of "ADM trypsinogens" and ductal markers. Additionally, this method enabled immune phenotyping via flow cytometry in a pancreatic ductal adenocarcinoma model. By overcoming the challenges associated with isolating acinar cells, our method offers an improvement over existing protocols for obtaining live single cells from the pancreas, which specifically caters to a comprehensive characterization of acinar cell populations.

Keywords:  ADM; CP; DCTC; acinar cell heterogeneity; acute pancreatitis; flow cytometry; healthy mouse pancreas; molecular biology; scRNA-seq; single-cell isolation

DOI:  https://doi.org/10.1016/j.crmeth.2026.101415
PLoS One. 2026 ;21(4): e0345890

Differential regulation of p62-ubiquitin conjugates in neurons versus astrocytes during cellular stress.

David K Sidibe, Erin M Smith, Maeve L Spivey, Maria C Vogel, Sandra Maday.

Sequestosome 1/p62 (hereafter referred to as p62) is a multifunctional protein that orchestrates various cellular stress response pathways including autophagy, proteasome-mediated degradation, antioxidant defense, nutrient sensing, and inflammatory signaling. Mutations in distinct functional domains of p62 are linked with the neurodegenerative disease amyotrophic lateral sclerosis (ALS), underscoring its importance in neural cells. Neurons and astrocytes, two key cell types in the brain, perform distinct roles in brain physiology and thus encounter a unique landscape of cellular stress. However, how p62 is regulated in these cell types in response to various stress modalities remains largely unexplored. Several functions for p62 depend on its engagement with ubiquitinated substrates. Thus, we investigated how the regulation of p62-ubiquitin conjugates differs between neurons and astrocytes exposed to two stress modalities: lysosomal membrane damage and metabolic stress. Lysosomal damage triggered ubiquitin-dependent assembly of p62 puncta in both neurons and astrocytes. In contrast, nutrient deprivation elicited different responses between neurons and astrocytes. Neurons formed p62-ubiquitin structures more prominently and displayed a greater dependence on ubiquitin for p62 clustering. Together, these findings reveal cell-type-specific and stress-specific regulation of p62-ubiquitin conjugates, indicating that neurons and astrocytes can deploy distinct quality control strategies.

DOI: https://doi.org/10.1371/journal.pone.0345890
Autophagy. 2026 May;22(5): 877-880

The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.

Dimitra Dialynaki, Daniel J Klionsky.

  Skeletal muscle is a fundamental tissue as it is found throughout the body, sustains posture, and produces movement. Yet, skeletal muscle disorders, such as myopathies, affect a large percentage of the population, degrading an individual's quality of life. A recent study links myopathy progression to the decline in chaperone-mediated autophagy that occurs during aging. Underscoring the importance of a balanced CMA pathway in maintaining skeletal muscle function and integrity, the study also provides mechanistic insights into the pathways that are dysregulated due to defective CMA and presents an approach to reverse the age-dependent decline in this process.Abbreviations: ATP2A1, ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; CMA, chaperone-mediated autophagy; HSPA8, heat shock protein family A (Hsp70) member 8; LAMP2A, lysosomal associated membrane protein 2A.

Keywords:  Aging; calcium homeostasis; chaperone-mediated autophagy; mitochondrial homeostasis; myopathy; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2026.2627051
Cancer Res. 2026 Apr 20.

Prolonged KRAS-MAPK Inhibition Induces Interferon Signaling that Promotes Cell State Transition and Confers Therapeutic Vulnerabilities.

Ashenafi Bulle, Yali Chen, Huaping Li, Timothy Hung-Po Chen, Iftikhar Ali Khawar, Lin Li, Yu Wang, Peng Liu, Vikas Kumar Somani, Richard Kurupi, Yutong Geng, Ofejiro Blessing Pereye, Sapana Bansod, Son B Le, Marianna B Ruzinova, David D Tran, Kian-Huat Lim.

Acquired resistance limits the therapeutic efficacy of KRAS-MAPK inhibitors in pancreatic ductal adenocarcinoma (PDAC). As transcriptional plasticity and epithelial-to-mesenchymal transition (EMT) have been implicated in resistance, we sought to study the molecular mechanisms driving these changes to uncover actionable vulnerabilities. Sustained KRAS-MAPK inhibition induced interferon and NF-κB signaling and promoted cell state change mimicking an EMT state associated with drug resistance. Network analysis identified the interferon-inducible E3 ubiquitin ligase TRIM22 as a central regulator of this response. Mechanistically, TRIM22 promoted proteasomal degradation of IκBα, resulting in sustained NF-κB and EMT program activation that coincided with a basal-like transcriptional cell state. TRIM22 expression was driven by IRF1 and IRF9 following relief of ERK-mediated transcriptional repression during pathway inhibition. EMT induction was accompanied by marked upregulation of TROP2 (TACSTD2), an NF-κB target gene enriched in basal-like PDAC cell states. Combining TROP2-directed antibody-drug conjugate sacituzumab govitecan with KRAS or ERK inhibitors significantly suppressed PDAC tumor growth in xenograft models. Overall, prolonged KRAS-MAPK inhibition activates an interferon-TRIM22-NF-κB axis that drives EMT and therapeutic resistance in PDAC, while revealing TROP2 as a clinically actionable vulnerability to overcome acquired resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4114
Biomech Model Mechanobiol. 2026 Apr 24. pii: 40. [Epub ahead of print]25(3):

Homeostatic pressure of a proliferating multicellular foam with hydromechanical volume regulation.

Jef Vangheel, Jeroen Guillierme, Irish Senthilkumar, Enda Howley, Eoin McEvoy, Bart Smeets.

  The dynamics of tumor growth and its competition with host tissue depend not only on proliferation rates but also on the mechanical properties of individual cells. Here, we present a hydromechanical model that couples osmotic volume regulation to tissue mechanics, representing multicellular aggregates as a proliferating foam of interacting cells. In confined conditions, we simulate multicellular growth until reaching a hydromechanical steady-state with a compressive multicellular stress. Next, we show that both increased adhesive tension and reduced surface tension increase the homeostatic pressure of a growing aggregate. This mechanical advantage allows softer and more adhesive cells to outcompete stiffer and even faster-growing populations. Our results demonstrate that single-cell mechanics can override proliferation rate in determining growth dynamics and competitive outcomes in multicellular aggregates.

Keywords:  Cell volume regulation; Deformable cell model; Homeostatic pressure; Hydromechanical; Proliferating foam model; Tissue growth

DOI:  https://doi.org/10.1007/s10237-026-02068-4
Front Bioeng Biotechnol. 2026 ;14 1735980

Histological fidelity and microenvironmental kinome signatures of metastatic patient-derived organoids.

Joana Leitão-Castro, Alexia Melanie Lopresti, Kamilla Westarp Zornhagen, Reidar Albrechtsen, Juan Camacho-Roda, Mille Bylov Ravn, Alejandro Gutierrez Martinez, Luis Arnes Perez, Eric Santoni-Rugiu, Martin Højgaard, Kristoffer Staal Rohrberg, Ulrik Lassen, Janine Terra Erler.

  Metastatic cancer remains the greatest clinical challenge due to ineffective treatments and limited reliable models for drug testing. Patient-derived organoids (PDOs) and their subsequent culture as patient-derived-organoid xenograft (PDOX) tumours have transformed cancer research by replicating the genetic and histological characteristics of primary tumours. However, less focus has been given to metastatic tumours. Here, we investigated how well kinase signalling was conserved in PDOs grown from core-needle biopsies isolated from metastatic tumour lesions of five cancer patients. We further compared changes in kinase signalling when these PDOs were grown as metastatic PDOX tumours in mice. Strikingly, PDOs retained much kinase signalling observed in the original tumour. Even more remarkable was the ability of the metastatic PDOX tumours to match both the signalling and morphological features of the original biopsy. Cross-sample analysis revealed lost Src Family Kinase signalling in PDO cultures, highlighting the important influence of the tumour microenvironment on signalling and demonstrating this can be partially restored in the in vivo setting. Together, these studies support the use of PDOs and derived PDOX in mimicking and modelling human metastatic tumour biology.

Keywords:  kinome; metastasis; organoids; precision medicine; tumour microenvironment

DOI:  https://doi.org/10.3389/fbioe.2026.1735980
J Cell Biol. 2026 May 04. pii: e202604009. [Epub ahead of print]225(5):

A pressure relief valve for lysosomes.

Layla M Nassar, Shawn M Ferguson.

Several mechanisms repair damaged lysosomal membranes, but how can lysosomes prevent membrane failure in the first place? Kim et al. (https://doi.org/10.1083/jcb.202509180) uncover a rapid response whereby TMEM63A-dependent ion efflux relieves membrane tension, buying time for slower repair mechanisms to engage.

DOI: https://doi.org/10.1083/jcb.202604009
Biochem Biophys Rep. 2026 Jun;46 102571

Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.

Christina Keller, Sebastian Rading, Bahar Candur, Laura Bindila, Gabriele Loers, Meliha Karsak.

  The endocannabinoid system (ECS) and the autophagy receptor p62 are both implicated in metabolic regulation and obesity, yet the mechanisms linking these pathways remain unclear. Here, we investigated whether p62 modulates CB1 receptor (CB1R) turnover or function and whether CB1R contributes to the metabolic phenotype of p62 knockout (KO) mice. In primary cortical neurons from wild-type mice, inhibition of autophagic flux with Bafilomycin A1 led to substantial CB1R accumulation, demonstrating that CB1R is a subject to autophagy-dependent degradation. CB1R agonist stimulation partially reduced this accumulation, suggesting receptor activation influences turnover. In vivo, p62 deficiency did not significantly alter CB1R protein abundance in the brain or hypothalamus, although hypothalamic ERK1/2 signaling downstream of CB1R was modestly attenuated. P62 KO mice displayed late-onset obesity without hyperphagia, early hypoactivity, and elevated hypothalamic 2-arachidonoylglycerol (2-AG) levels with age. Fasting-refeeding experiments revealed reduced food intake in adult and aged, but not juvenile, p62 KO animals. Pharmacological CB1R antagonism did not uncover a direct receptor-dependent mechanism underlying these phenotypes. Together, these findings indicate that, although CB1R undergoes autophagic degradation in neurons, p62 deficiency does not alter steady-state receptor levels and does not directly account for obesity or hypoactivity in p62 KO mice. Within the scope of the experiments performed, CB1R is therefore unlikely to be a primary driver of the metabolic phenotype associated with p62 deficiency.

Keywords:  Autophagy; CB1 receptor; Endocannabinoid system; Fasting; Locomotor activity; Obesity; p62

DOI:  https://doi.org/10.1016/j.bbrep.2026.102571
J Proteomics. 2026 Apr 21. pii: S1874-3919(26)00063-1. [Epub ahead of print] 105660

Proteomic characterization of primary pancreatic fibroblasts derived from neoadjuvant chemotherapy treated versus treatment-naïve PDAC.

Manoj Amrutkar, Anette Vefferstad Finstadsveen, Knut Jørgen Labori, Caroline S Verbeke, Ivar P Gladhaug.

  Neoadjuvant chemotherapy (NAT) is increasingly used in the treatment of pancreatic ductal adenocarcinoma (PDAC). However, the actual molecular impact of NAT on the tumor remains unknown, particularly on the cancer-associated fibroblasts (CAFs) remains largely unknown. Here, mass-spectrometry (MS)-based proteomic profiling of primary CAFs derived from treatment-naïve (TN) and NAT-treated resected PDAC (n = 10 in each group) was conducted to explore potential NAT-associated changes. Differentially abundant proteins (DAPs; p < 0.05) in NAT versus TN CAFs accounted for 10.6% of all 5438 proteins mapped by MS. According to gene ontology analysis, DAPs with higher abundance (273) in NAT versus TN were involved in protein transport and carbohydrate metabolism, while DAPs with lower abundance (305) were mainly related to RNA processing. Protein-protein interactions identified several cluster networks of closely linked DAPs. Exploring the correlation between DAPs abundance and survival identified a negative correlation for 30 of 42 DAPs in NAT group. In addition, several proteins were found to be differentially abundant among different NAT regimens. In conclusion, this exploratory study reveals significant NAT-associated changes in CAF proteome profiles, which are related to the fundamental biological processes of RNA processing and protein transport. Further validation of these preliminary findings using a large independent cohort is needed.

Keywords:  Cancer-associated fibroblasts; Neoadjuvant chemotherapy; Pancreatic cancer; Proteomics

DOI:  https://doi.org/10.1016/j.jprot.2026.105660
Nat Cell Biol. 2026 Apr 23.

A lipid-centric view of endocytosis by caveolae.

Robert G Parton, Michael M Kozlov, Richard Lundmark.

Caveolae have long been considered to be an alternative endocytic pathway, with distinct cargoes, but generally similar functions, to clathrin-coated pits. Here we suggest that the mechanisms of caveola formation and their scission are tightly interlinked and rely on specific lipids. These mechanisms are fundamentally different to those driving the formation and fission of coated pits. Both formation and scission of caveolae are driven by lipid-induced shaping of the caveolar domain, and we present biophysical models for lipid-driven curvature generation and its coupling with scission. In addition, we propose that these new insights have important implications for understanding the function of endocytosis mediated by caveolae. Rather than a parallel endocytic pathway for protein cargo, we argue that caveolae are a lipid-sensitive mobilized multifunctional surface domain.

DOI: https://doi.org/10.1038/s41556-026-01945-5
Cell Syst. 2026 Apr 20. pii: S2405-4712(26)00071-2. [Epub ahead of print] 101589

Cell shapes decode molecular phenotypes in image-based spatial proteomics.

Trang Le, William D Leineweber, Matheus P Viana, Anthony Cesnik, Jan N Hansen, Wei Ouyang, Susanne M Rafelski, Emma Lundberg.

  Cellular and tissue structures arise from a few cell shapes, which undergo transformations based on biophysical constraints. Despite links between signaling pathways and cellular geometry, whole-proteome orchestration in association with cell shape is underexplored. In this study, over 1 million single cells stained for 11,998 proteins across 11 cell lines in the Human Protein Atlas were analyzed for organelle, pathway, and single-protein levels in association with cellular shapespace. We found that cell and nuclear shapes across cell lines exist in a shared continuum. The subcellular organelle topology varies across cell lines but remains consistent within each cell line's shapespace. At the single-protein level, cells of different shapes in the same cell-cycle phase might be preparing for different fates, and many non-cell-cycle proteins expressed shape-based abundance variation. Using a shape-based coordinate framework, we analyzed the distribution shift of protein spatial localization under drug perturbation.

Keywords:  cell shape; interpretable machine learning; molecular variation; morphological variation; single cell; spatial proteomics

DOI:  https://doi.org/10.1016/j.cels.2026.101589
Cell Discov. 2026 Apr 21. pii: 28. [Epub ahead of print]12(1):

ASO-based PKM splice-switching therapy increases anti-CTLA-4 antibody efficacy in pancreatic ductal adenocarcinoma.

Lijie Han, Lina Gan, Balázs Schäfer, Dillon M Voss, Mathias Danielsen, Ondrej Kostov, Jia Liu, Ting Wang, Marvin H Caruthers, Hao Chen, Adrian R Krainer.

The alternative splice isoform of pyruvate kinase M (PKM), PKM2, plays a pivotal role in regulating aerobic glycolysis in tumor cells. Systemic delivery of antisense oligonucleotides (ASOs) that shift PKM splicing from the PKM2 isoform to the PKM1 isoform inhibits tumor progression and reprograms intratumoral metabolism. However, the cellular populations within the tumor microenvironment (TME) are also highly dependent on PKM2 and might likewise be affected by ASO treatment. In this study, we demonstrate that PKM2 is upregulated and PKM1 is downregulated in both human and murine pancreatic ductal adenocarcinoma (PDAC) cells. PKM1 and PKM2 are mutually exclusive and expressed in a cell type-specific manner in various cell types and stages of PDAC tumors. We report that basal-like PDAC cells and their surrounding activated regulatory T cells (Tregs) rely on PKM2 to sustain glycolysis. Although PKM-ASO monotherapy had a limited effect in an immunodeficient mouse model of PDAC, synergy between PKM-ASO and anti-CTLA-4 immune checkpoint blockade (ICB), which targets Tregs, restricted tumor growth in an immunocompetent mouse model. Our findings provide preclinical support for combined antisense therapy and ICB for PDAC patients, highlighting the critical role of PKM2 in the TME and its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41421-026-00882-9
Nat Cancer. 2026 Apr 24.

Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity.

Raul Jimenez-Castaño, M Angela Nieto.

Epithelial-to-mesenchymal transition (EMT) is a central driver of cancer cell plasticity, enabling invasion, immune evasion, therapeutic resistance and metastasis. Rather than a binary switch, EMT comprises a continuum of transient, reversible states that endow tumor cells with distinct functional properties. Recent technological advances have revealed an unexpected diversity of EMT states across tumor contexts, with implications for disease progression and therapy response. In this Review, we synthesize emerging evidence on EMT heterogeneity and dynamics during cancer progression, examine how new methodologies have increased our understanding of the process and outline therapeutic challenges and opportunities.

DOI: https://doi.org/10.1038/s43018-026-01154-x
Nature. 2026 Apr 22.

Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer.

Gael Roth, Pascal Artru, Olivier Bouche, Nicolas Williet, Julien Ghelfi, Anthony Turpin, Astrid Lievre, Jean-Frédéric Blanc, Camille Evrard, Jean-Baptiste Bachet, Pauline Parent, Marc Manceau, Matthieu Roustit, Anna Borowik, Victoire Granger, Aurélie Durand, Christelle d'Engremont, Edouard Girard, Mircea Chirica, Nicolas Braissand, Nicolas Rama, Eugénie Modolo, Hector Hernandez-Vargas, Elise Georges, Jean-Yves Scoazec, Jerome Cros, Sébastien Hazard, Benjamin Ducarouge, Thomas Decaens, Agnès Bernet, Patrick Mehlen.

Netrin1, a developmental cue, is a master regulator of tumour epithelial-to-mesenchymal transition (EMT)1, a mechanism that is known to drive resistance to chemotherapy2. A netrin1 antibody (NP137)3 has been shown to inhibit tumour EMT in preclinical1 and clinical4 settings. In animal models of pancreatic cancer, netrin1 and its receptor neogenin have been shown to promote tumour progression5, EMT5 and metastasis6. Here we report the results of a phase 1b study that assesses the combination of NP137 with modified FOLFIRINOX (mFOLFIRINOX) in first line patients with locally advanced pancreatic cancer (ClinicalTrials.gov: NCT05546853 ). Forty-three patients were enrolled and received mFOLFIRINOX plus NP137 every other week for up to 12 cycles. NP137 was well tolerated. Median progression-free survival (PFS) was 10.85 months (95% confidence interval, 10.03-15.61) and median overall survival was 16.43 months (95% confidence interval, 12.75-non-reached), with 21 patients remaining alive at the time of data cut-off. Post-therapy conversion surgery occurred in 23% of patients. Laser capture microdissection was performed on pre-therapeutic biopsies and surgical specimens. Microbulk RNA sequencing confirmed that the main pathway that was down-regulated with the combination of mFOLFIRINOX plus NP137 was EMT. Moreover, survival outcomes were extended for patients with tumour cells that expressed high levels of the netrin1 receptor neogenin-median PFS 15.65 months in neogenin-high versus 10.22 months in neogenin low. Our results support the idea that netrin1 blockade alleviates resistance to chemotherapy by inhibiting EMT, particularly in neogenin-high pancreatic cancer.

DOI: https://doi.org/10.1038/s41586-026-10436-4
Biointerphases. 2026 Mar 01. pii: 020801. [Epub ahead of print]21(2):

Mimicking nature: Models of lipid membranes created with the Langmuir monolayer technique: A review of lipid membrane composition.

Patrycja Dynarowicz-Latka, Anita Wnętrzak, Anna Chachaj-Brekiesz, Vladislav Maliugin.

The Langmuir monolayer technique has proven to be an effective method for constructing lipid-based models of cell membranes. Compared to other artificial membrane systems, such as liposomes or supported lipid bilayers, it offers a relatively simple and versatile approach to reconstructing lipid components of biological membranes and systematically modifying their composition. The technique allows precise control over experimental parameters such as surface pressure and temperature, which influence the physical state and organization of lipid monolayers. Lipid monolayer models are widely used to investigate molecular interactions at membrane interfaces, including the effects of biomolecules or xenobiotics on membrane properties, identification of potential molecular targets of drugs, and evaluation of mechanisms underlying their pharmacological activity or toxicity. While the successful application of the monolayer technique in lipid membrane modeling has been extensively reported in the literature, comprehensive discussions of lipid compositions for modeling various membrane types-such as eukaryotic, prokaryotic, viral, and pathological membranes-remain limited. In particular, systematic descriptions of lipid mixtures used to model membranes characteristic of eukaryotic cells, prokaryotes, viruses, or pathological states are limited. The aim of this review is to address this gap by summarizing lipid compositions used in Langmuir monolayer models designed to mimic different biological membrane types.

DOI: https://doi.org/10.1116/6.0005379