bims-cagime 2026-02-15 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–02–15
37 papers selected by
Kıvanç Görgülü, Technical University of Munich

Dietary Fat Content Influences PanIN Progression and Pancreatic Cancer Development in Mice.
Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.
Metabolic permissiveness: how tissue context shapes cancer.
Dual pancreatic carcinomas: clonally related or independent primaries?
Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models.
Decoding Membrane Lipids: Analytical Barriers and Technological Advances in Modern Lipidomics.
Impact of lipid asymmetry on membrane biophysical properties: Insights from molecular dynamics simulations.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
PRMT5 inhibitors actively promote metastatic progression of lung adenocarcinoma.
Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer.
Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours.
Relocation of Endocytic Leaflet DNA Probes for Asymmetric and Week-Long Lysosomal Labeling.
Regorafenib enhances anti-PDCD1/PD-1 therapeutic efficacy in colorectal cancer by promoting SQSTM1/p62-mediated CD274/PD-L1 degradation.
Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial.
Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death.
Mammalian lipophagy: process and function.
Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression.
Rapid optogenetic manipulation of autophagy reveals that the nuclear pore complex is a robust autophagy substrate.
Physical activity and metabolic rates in humans.
ImmunoPheno: A Computational Framework for Data-Driven Design and Analysis of Immunophenotyping Experiments.
MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.
CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1.
International Multidisciplinary Consensus Report on Definitions, Diagnostic Criteria, and Management of Fatty Pancreas: A Joint Statement Endorsed by EPC, APA, EASD, EASL, ESGAR, ESGE, ESP, ESPCG, ESPEN, ESPGHAN, IAP, JPS, KPBA, LAPSG, and UEG.
CLISGen: A Comprehensive Resource of SNP Genotypes for Human Cell Lines.
CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response.
Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.
Cohort-Scale Spatial Autocorrelation for Tumor Prediction in Mid-Infrared Pathology and Spatial Biomarker Discovery Using MALDI Imaging Lipidomics.
Monitoring senescent cell dynamics in wound healing using a p16-tdtomato mouse model.
SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.
SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.
Autophagy in kidney physiology: from cellular quality control to organ metabolism.
AutoMorphoTrack: A modular framework for quantitative analysis of organelle morphology, motility, and interactions at single-cell resolution.
β-Adrenergic Signaling Promotes Anti-Tumor Immunity in TP53-mutant Oral Squamous Cell Carcinoma.
The aging mouse lipidome.
Negative feedback regulation of STING signaling by TAX1BP1-directed Golgiphagy.
NALIRIFOX versus nab-paclitaxel and gemcitabine in older patients with treatment-naive metastatic pancreatic cancer: a subgroup analysis of the pivotal NAPOLI 3 trial.
Molecular origins of viscoelasticity in biomolecular condensates.

bioRxiv. 2025 Dec 01. pii: 2025.11.26.690783. [Epub ahead of print]

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, 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 Ptf1a CreERT2 ;Kras G12V (Acinar KrasG12V ) mouse model. KD-fed mice showed the shortest survival (median 26 ± 7 days) compared with 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 induced severe glucose intolerance and elevated circulating β-hydroxybutyrate levels. Histologically, KD-fed Acinar KrasG12V mice developed invasive, sarcomatoid-like pancreatic ductal adenocarcinoma (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 in KD and HFD-fed Acinar KrasG12V mice. Serum cytokines/chemokines profiling revealed pro-inflammatory and pro-angiogenic milieu in KD-fed Acinar KrasG12V mice. Collectively, these results show that dietary lipid enrichment prior to oncogenic Kras activation may accelerate early pancreatic neoplasia and foster 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/10.1101/2025.11.26.690783
Cancer Cell. 2026 Feb 12. pii: S1535-6108(26)00053-X. [Epub ahead of print]

Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.

Xiuhui Shi, Alex X Arreola, Zhijun Zhou, Jingxuan Yang, Mingyang Liu, Yang Cai, Yu Ren, Hao Yuan, Qun Chen, Xinjie Chen, Xinyu Yang, Yimei Meng, Jingyi Wang, Wenyi Luo, Michael C Rudolph, Rohan Varshney, Kar-Ming Fung, Chao Xu, Wei R Chen, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li.

  Cancer-induced cachexia and anorexia are debilitating complications across many cancers, yet effective treatments remain limited due to a poor understanding of the underlying mechanisms. Here, we identify an uncharacterized tumor-immune-neural circuit driving these syndromes, centered on growth and differentiation factor 15 (GDF15). Using genetically engineered mouse models, we find that loss of GDF15 protects against appetite loss, muscle wasting, and fat loss in pancreatic, lung, and skin cancers. Single-cell RNA sequencing reveals macrophages as a major source of GDF15, induced by tumor-derived colony-stimulating factor 1 (CSF1). GDF15 acts via the central nervous system to enhance β-adrenergic signaling in the tumor microenvironment, thereby amplifying cachexia. The disruption of this feedforward loop with GDF15-neutralizing antibody, anti-CSF1R antibody, or Rearranged during Transfection (RET) inhibitor markedly reduces both cachexia and anorexia. These findings reveal a non-cell-autonomous mechanism linking tumor signals, macrophage-derived GDF15, and neural pathways, highlighting the tumor-immune-neural triad as a promising therapeutic target.

Keywords:  adipose loss; body composition; energy expenditure; hormone; metabolic stress; muscle atrophy; norepinephrine; sympathetic nerve; tumor immune microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2026.01.014
Genes Dev. 2026 Feb 09.

Metabolic permissiveness: how tissue context shapes cancer.

Chrysanthi Moschandrea, Christian Frezza.

  An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.

Keywords:  cancer; metabolism; permissiveness

DOI:  https://doi.org/10.1101/gad.353516.125
NPJ Precis Oncol. 2026 Feb 08.

Dual pancreatic carcinomas: clonally related or independent primaries?

Joshua D Schoenfeld, Vignesh Ravichandran, Zeynep Tarcan, Hulya Sahin-Ozkan, Allison L Richards, Nadeem Bilani, Joanne F Chou, Catherine A O'Connor, David McManamon, Anna M Varghese, Fergus Keane, Michael I D'Angelica, William R Jarnagin, Jeffrey Drebin, Diane Reidy-Lagunes, Alice C Wei, Sree B Chalasani, Fiyinfolu Balogun, Wungki Park, Kenneth H Yu, Kevin Soares, Mark T A Donoghue, Christine Iacobuzio-Donahue, Zsofia K Stadler, Marinela Capanu, Olca Basturk, Eileen M O'Reilly.

Dual pancreatic cancers, either synchronous or metachronous in presentation, are a rare occurrence. It remains unclear if these lesions are clonally related or independently occurring primary malignancies. Herein we present a cohort (N = 22) with dual pancreatic ductal adenocarcinoma (PDAC) tumors to resolve previously conflicting reports and interrogate the underlying biological and clinical characteristics of this patient population. Next-generation sequencing of paired lesions (N = 10) revealed that while most dual PDAC are clonally related, independently occurring lesions do occur, irrespective of the interval between lesions. Integrated clinical, genomic, and histopathological analyses revealed a high frequency of lymph node-negative, intraductal papillary mucinous neoplasm (IPMN)-associated cancers, KRAS and/or SMAD4 wild-type tumors, and classical subtype by immunohistochemistry, all collectively associated with more favorable outcomes. Acknowledging the highly selected nature of this cohort, isolated intrapancreatic metastases demonstrate a more indolent biology and these patients may benefit from personalized management approaches beyond traditional paradigms.

DOI: https://doi.org/10.1038/s41698-026-01313-4
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702341. [Epub ahead of print]

Endothelial Cell Autophagy Suppresses Metastasis In Mouse Mammary and Pancreatic Neuroendocrine Tumor Models.

Nancy León-Rivera, Brayden Chin, Ashley Quintana, Sofia Bustamante-Eguíguren, Anthony Gacasan, Monica Nanni, Jayanta Debnath, Teresa Monkkonen.

Autophagy, a key lysosomal degradation pathway regulating metabolic adaptation in cancer, plays fundamental roles in both the tumor and host stromal compartments during cancer progression. An important unanswered question is whether and how autophagy in specific host stromal elements, such as endothelial cells, influences metastasis. Here, we scrutinize how the genetic loss of autophagy in endothelial cells impacts primary tumor progression and metastasis in the Polyoma Middle T ( PyMT ) model of luminal B breast cancer. In both autochthonous and orthotopic mammary transplant models, PyMT primary tumor growth is significantly delayed upon endothelial cell Atg12 or Atg5 genetic deletion ( Atg12 or 5 ECKO), which correlates with increased tumor cell apoptosis and HIF1α activation. In contrast, PyMT -bearing Atg12 ECKO mice exhibit increased metastasis, as well as higher rates of primary tumor and lung metastatic recurrence following surgical resection of PyMT primary tumors. Experimental metastasis assays further corroborate that loss of endothelial cell autophagy in Atg12 ECKO host animals promotes PyMT metastatic colonization and outgrowth, resulting in increased lung metastases compared to controls. Similarly, in the Rat Insulin Promoter T antigen pancreatic neuroendocrine tumor (RT2-PNET) model, endothelial cell deletion of Atg12 promotes liver micro-metastases. Taken together, these results from distinct preclinical cancer models reveal that endothelial cell autophagy suppresses metastatic seeding and progression and broach that autophagy inhibition in host endothelial cells may adversely influence the efficacy of systemic autophagy-lysosomal pathway inhibition in the clinical oncology setting.

DOI: https://doi.org/10.64898/2026.01.28.702341
Int J Mol Sci. 2026 Feb 02. pii: 1472. [Epub ahead of print]27(3):

Decoding Membrane Lipids: Analytical Barriers and Technological Advances in Modern Lipidomics.

Kyung-Hee Kim, Byong Chul Yoo.

  Biological membranes are dynamic, information-rich platforms whose structural and functional properties are dictated by lipid composition rather than acting as passive barriers. Recent advances in lipidomics have revealed that variations in lipid headgroups, acyl-chain length and saturation, sn-positional architecture, and oxidative modifications profoundly influence membrane mechanics, lateral organization, and protein-lipid interactions. These features collectively regulate fundamental cellular processes, including signaling, trafficking, curvature generation, and transbilayer asymmetry. In parallel, a wide range of pathological conditions-including cancer, metabolic disorders, neurodegeneration, and inflammatory diseases-are increasingly associated with coordinated lipid remodeling that reshapes membrane material properties and electrostatic landscapes. In this review, we integrate biophysical principles with lipidomics-based evidence to elucidate how lipid chemical diversity translates into membrane-level behavior. We discuss the roles of major membrane lipid classes, the functional consequences of acyl-chain and sn-positional remodeling, and the biological significance of lipid asymmetry and lateral heterogeneity. Particular attention is given to disease-associated lipid reprogramming and extracellular vesicle lipidomes as functional extensions of cellular membranes. Finally, we examine key analytical barriers in modern lipidomics and outline strategies required to connect lipid structural information with biological function. Together, this framework highlights membrane lipid architecture as a central determinant of cellular physiology and a promising axis for mechanistic insight and translational biomarker discovery.

Keywords:  acyl-chain composition; ceramides; extracellular vesicle; lipid rafts; lipidomics; membrane asymmetry; membrane curvature; membrane lipids; phosphatidylserine; phospholipid remodeling

DOI:  https://doi.org/10.3390/ijms27031472
Quant Biol. 2025 Jun;13(2): e89

Impact of lipid asymmetry on membrane biophysical properties: Insights from molecular dynamics simulations.

Yong Zhang, Jizhong Lou.

  Asymmetry between outer and inner leaflets of cell membrane, such as variations in phospholipid composition, cholesterol (CHOL) distribution, stress levels, and ion environments, could significantly influence the biophysical properties of membranes, including the lateral organization of lipids and the formation of membrane nanodomains. To elucidate the effects of lipid component, lipid number mismatch, CHOL concentration asymmetry, and ionic conditions on membrane properties, we constructed several sets of all-atom, multi-component lipid bilayer models. Using molecular dynamics (MD) simulations, we investigated how membrane asymmetry modulates its biological characteristics. Our results indicate that CHOL concentration, whether symmetric or asymmetric between the leaflets, is the primary factor affecting membrane thickness, order parameters of the lipid tail, tilting angles of lipid molecules, water permeability, lateral pressure profiles, and transmembrane potential. Both low and high CHOL concentrations significantly alter lipid bilayer properties. Inducing cross-leaflet stress by mismatching lipid numbers can modify lipid order parameters and the tilting angles but has only mild effect on lateral pressure profiles and membrane thickness. Additionally, we found that transmembrane potential, generated by ions concentration differences across the membrane, can influence water permeability. Our findings expand the current understanding of lipid membrane properties and underscore the importance of considering CHOL and phospholipid asymmetry in membrane biophysics. The membrane models developed in our study also provide more physiological conditions for studying membrane proteins using MD simulations.

Keywords:  cholesterol distribution; membrane asymmetry; membrane electrostatic potential; membrane pressure; molecular dynamics simulation

DOI:  https://doi.org/10.1002/qub2.89
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
bioRxiv. 2026 Feb 02. pii: 2026.01.30.702866. [Epub ahead of print]

PRMT5 inhibitors actively promote metastatic progression of lung adenocarcinoma.

Colin E Fowler, Natalie A O'Hearn, Nicole Henning, Anthony Griffen, Nicolas Mathey-Andrews, Griffin J Salus, Renin Hazan, Tyler Jacks, Aurora A Burds, Helen S Mueller, Yadira Soto-Feliciano, Lindsay M LaFave, Jacqueline A Lees.

Epigenetic changes are a major driver of cancer progression, placing considerable focus on epigenetic regulators as therapeutic targets. Protein arginine methyltransferase 5 (PRMT5) is one such regulator, and numerous PRMT5 inhibitors (PRMT5i) in clinical trials. Despite this, the mechanisms and consequences of PRMT5i-resistance are unknown. Here, we demonstrate that aggressive cancer progression is an inbuilt feature of PRMT5i-resistance acquisition in lung adenocarcinoma (LUAD). Independently-generated resistant cell lines gain dedifferentiation signatures that typify late-stage disease and show increased metastatic potential in vivo . We establish that these state shifts are a direct consequence of PRMT5i action; treatment induces rapid and widespread chromatin rewiring, enabling derepression of late-stage disease states that are stably established in resistant cells. Notably, treatment of lung tumor-bearing mice drives rapid disease advancement without decreasing tumor burden, showing that drug-induced disease progression supersedes any benefits from PRMT5 inhibition in vivo . Furthermore, analyses of human cell lines and patient cohorts supports the notion of PRMT5 inhibition-mediated dedifferentiation. Collectively our data show that PRMT5i can actively promote self-resistance and disease progression in different tumor types. This raises serious concerns for the use of PRMT5i in patients, arguing that clinical studies should consider the possibility of drug-induced plasticity, resistance, and disease advancement.

DOI: https://doi.org/10.64898/2026.01.30.702866
Nat Commun. 2026 Feb 07.

Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer.

Yu C J Chey, Bassam Kashgari, Louise McLeod, Georgette A Radford, Linden J Gearing, Ruby E Dawson, Malvika Kharbanda, Joanne Lundy, Daniel Croagh, Charlotte Girard-Guyonvarc'h, Cem Gabay, Brooke A Pereira, David Herrmann, Paul Timpson, John W Finnie, Mohamed I Saad, Dharmesh D Bhuva, Bernardo S Franklin, Florian I Schmidt, Brendan J Jenkins.

Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.

DOI: https://doi.org/10.1038/s41467-026-69398-w
Nat Biomed Eng. 2026 Feb 11.

Ablation of prostaglandin E2 signalling through dual receptor knockout in CAR T cells enhances therapeutic efficacy in solid tumours.

Janina Dörr, Lisa Gregor, Sebastian B Lacher, Arman Oner, Yi Sun, Ignazio Piseddu, Luisa Fertig, Sebastijan Spajic, Stefanie Lesch, Stefanos Michaelides, Matthias Seifert, Adrian Gottschlich, Natasha Samson, Lina Majed, Daria Briukhovetska, Donjetë Simnica, Viktoria Hartmann, Kathrin Gabriel, Sonia Cohen, Genevieve M Boland, David Andreu-Sanz, Emanuele Carlini, Sophia Stock, Anne Holtermann, Philipp Jie Müller, Thaddäus Strzalkowski, Marcel P Trefny, Stefan Endres, Russell W Jenkins, Jan P Böttcher, Sebastian Kobold.

The efficacy of chimeric antigen receptor (CAR) T cell therapy in solid cancers is limited by immunosuppression in the tumour microenvironment (TME). Prostaglandin E2 (PGE2) is a key factor locally inhibiting T cell function. We hypothesized that targeted ablation of PGE2 signalling in CAR T cells may enhance their activity in PGE2-rich solid tumours. Here we generate knockout CAR T cells double deficient for the PGE2 receptors EP2 and EP4 (EP2-/-EP4-/-) by CRISPR-Cas9 engineering. EP2-/-EP4-/- CAR T cells expanded unabatedly in the presence of PGE2. Further, they effectively controlled syngeneic and human xenograft tumour models in vivo, which was accompanied by intratumoural accumulation and persistence of modified T cells. Improved anti-tumour activity was also observed against patient-derived tumour samples from patients with pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC) and neuroendocrine (NET) cancer. Our data uncovers the detrimental impact of PGE2-mediated suppression on CAR T cell efficacy and highlights EP2 and EP4 targeting as a potential strategy.

DOI: https://doi.org/10.1038/s41551-025-01610-6
J Am Chem Soc. 2026 Feb 10.

Relocation of Endocytic Leaflet DNA Probes for Asymmetric and Week-Long Lysosomal Labeling.

An Yan, Yuhan Kong, Yuxing Shang, Yifan Ge, Hang Xing, Di Li.

Visualization of lysosomes in living cells is essential for understanding their physiological functions; yet, most probes that target the lysosomal interior often disrupt luminal chemistry, exhibit signal leakage, and fail to support long-term imaging. To address these challenges, we developed RELAY (Relocation of Endocytic Leaflet tAg to modifY organelles), a topology-preserving labeling strategy to transfer the inner-leaflet tags on the plasma membrane to the cytosol-facing outer leaflet of lysosomes. RELAY employs liposome-cell membrane fusion to anchor fluorescent DNA probes with phosphorothioate (PS) backbones on the cytoplasmic inner leaflet of the plasma membrane, followed by endocytic trafficking that preserves the membrane topology and relocates the probes onto the lysosomal outer surface. Because this labeling occurs on the lysosomal exterior that is protected from luminal degradation and the PS backbone resists nuclease degradation, RELAY enables highly stable asymmetric labeling that sustains week-long lysosome imaging in living cells. Using this approach, we visualized lysosomal dynamics during cellular senescence and discovered random, unidirectional, intercellular lysosomal transfer in cell-cell communications via tunnelling nanotubes. Holding the capability for prolonged, high-fidelity visualization of lysosomes, RELAY facilitates the exploration of their biological functions.

DOI: https://doi.org/10.1021/jacs.5c21974
Autophagy. 2026 Feb 08.

Regorafenib enhances anti-PDCD1/PD-1 therapeutic efficacy in colorectal cancer by promoting SQSTM1/p62-mediated CD274/PD-L1 degradation.

Ming Zhu, Yinjun He, Siqin Lei, Xuan Lai, Chaoyi Chen, Kehong Ye, Dianyang Li, Honghe Zhang, Maode Lai, Weiqin Jiang.

  Despite the clinical success of PDCD1/PD-1 and CD274/PD-L1 immune checkpoint blockade in multiple cancers, its efficacy in colorectal cancer (CRC) remains limited. Here, we report that the combination of the tyrosine kinase inhibitor regorafenib with PDCD1 blockade enhances anti-tumor immunity in CRC, both in clinical observations and preclinical models. Mechanistically, regorafenib acts as a molecular glue, directly promoting the interaction between CD274 and the selective autophagy receptor SQSTM1/p62, leading to SQSTM1-mediated autophagic degradation of CD274 and restoration of T cell-mediated cytotoxicity. In summary, these findings identify a previously unrecognized role of regorafenib in modulating tumor immune evasion and provide a mechanistic rationale for its combination with PDCD1 inhibitors in CRC treatment.

Keywords:  Antitumor immunity; PD-L1; molecular glue; p62; protein degradation; regorafenib

DOI:  https://doi.org/10.1080/15548627.2026.2629288
Nat Commun. 2026 Feb 10. 17(1): 1538

Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial.

Amanda L Huff, S Daniel Haldar, Alexander A Gergis, Hejia Henry Wang, Ludmila Danilova, Thatcher Heumann, Maureen Berg, Yuxuan Wang, Lalitya Andaloori, Alexei Hernandez, Gabriella Longway, Benjamin Barrett, Zirui Zhu, Emily Davis-Marcisak, Christopher Thoburn, James Leatherman, Sarah Mitchell, Jae W Lee, Daniel H Shu, Maximillian F Konig, Brian J Mog, Janelle Montagne, Erin M Coyne, Katherine Bever, Marina Baretti, Mark Yarchoan, Robert A Anders, Luciane T Kagohara, Daniel Laheru, Amy M Thomas, Jennifer Durham, Julie M Nauroth, Jiayun Lu, Hao Wang, Elana J Fertig, Won Jin Ho, Nilofer S Azad, Elizabeth M Jaffee, Neeha Zaidi.

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

DOI: https://doi.org/10.1038/s41467-026-68324-4
Cell Rep. 2026 Feb 10. pii: S2211-1247(26)00042-2. [Epub ahead of print]45(2): 116964

Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death.

Koyuki Kawamura, Koya Ono, Eikan Mishima, Osamu Hashizume, Marcus Conrad, Hiroaki Miki, Yosuke Funato.

  Mg2+ is an essential cofactor for numerous enzymes, supporting fundamental cellular processes. The phosphatase of regenerating liver (PRL) protein family, frequently upregulated in cancer, inhibits cyclin M (CNNM) Mg2+ efflux transporters. To elucidate the physiological role of PRL in Mg2+ homeostasis at the cellular level, we employed combined genetic knockout and knockdown approaches. PRL deletion led to marked reduction of intracellular Mg2+ levels and triggered extensive cell death. Transcriptomic analysis revealed activation of the NF-κB pathway, and, accordingly, the genetic deletion of NF-κB p65 subunit abrogated cell death. Similarly, CNNM overexpression triggered intracellular Mg2+ decrease, NF-κB activation, and subsequent cell death. Notably, this form of cell death exhibited characteristic morphological features, including actin-driven fiber-like protrusions, distinguishing it from known cell death modalities. Our findings uncover a distinct mode of NF-κB-dependent cell death triggered by intracellular Mg2+ decrease.

Keywords:  CNNM; CP: cell biology; NF-κB; PRL; actin polymerization; magnesium; regulated cell death

DOI:  https://doi.org/10.1016/j.celrep.2026.116964
Autophagy. 2026 Feb 12.

Mammalian lipophagy: process and function.

Rui Zhao, Enyong Dai, Rui Kang, Jiao Liu, Daniel J Klionsky, Daolin Tang, Yangchun Qu, Yuanqiang Lin, Xinyue Zhang.

  Lipophagy, the selective autophagic degradation of lipid droplets (LDs), is a key mechanism for lipid homeostasis and cellular adaptation to metabolic and stress conditions. In mammals, lipophagy is governed by signaling pathways, LD-associated receptors (e.g. SQSTM1/p62, NBR1, OPTN, SPART, OSBPL8, DDHD2, VPS4A, ATG14, and TP53INP2), and transcription factors (TFEB, TFE3, FOXO1, PPARA, PPARG, and SREBF1/SREBP1) that coordinate LD recognition, sequestration, and lysosomal degradation. Dysregulated lipophagy contributes to the pathogenesis of metabolic and age-related diseases, including metabolic dysfunction-associated steatotic liver disease/nonalcoholic fatty liver disease (MASLD/NAFLD), alcoholic liver disease, diabetes, atherosclerosis, neurodegeneration and cancer. Several recent reviews have discussed lipophagy from different angles, including its roles in metabolic disorders, central nervous system diseases, and fundamental mechanisms across species. In contrast, this review focuses specifically on mammalian lipophagy by synthesizing the latest mechanistic insights into receptor-mediated recognition, transcriptional regulation, and signaling integration. We also outline unresolved questions and conceptual gaps - such as how lipophagy is selectively activated, how it coordinates with lipolysis, and whether distinct receptor codes exist in tissue- and disease-specific contexts - that remain unanswered in the current literature.

Keywords:  Autophagy receptor; disease; lipid droplets; lipophagy; transcription factor

DOI:  https://doi.org/10.1080/15548627.2026.2632256
Cancer Discov. 2026 Feb 09.

Myofibroblasts induce neuroplasticity to promote pancreatic inflammation and cancer progression.

Jérémy Nigri, Wenjun Lan, Melanie L Fung, Charlotte Kayser, Astrid Deschênes, Juliene Hinds, Sanjeev Kaushalya, Sara A Pawlak, Jennifer S Thalappillil, Sandeep Nadella, Marc Hilmi, Wungki Park, Rajya Kappagantula, Youngkyu Park, Zhen Zhao, Jonathan Preall, Christine A Iacobuzio-Donahue, Kevin J Tracey, Jeremy C Borniger, David A Tuveson.

Pancreatic ductal adenocarcinoma (PDAC) co-opts the peripheral nervous system through nerve hypertrophy, axonogenesis and perineural invasion, and these processes correlate with patient morbidity and mortality. Prior work has shown that autonomic nerves directly modulate neoplastic cells in PDAC, but whether cancer-associated fibroblasts (CAFs) participate in neural remodeling is unknown. Using thick tissue sections, we identified dense neo-innervation near myofibroblastic CAFs (myCAFs) in preinvasive Pancreatic Intraepithelial Neoplasms (PanINs). Mechanistically, TGF-β produced during inflammation and neoplasia triggers myofibroblast formation, and myCAFs produce axon guidance molecules that recruit sympathetic nerves. Norepinephrine released by sympathetic nerves activates myofibroblast cultures in vitro, and sympathetic nerve depletion impairs stromal activation and PDAC growth in vivo. A chemogenetic model confirmed that fibroblast-specific α1-adrenergic signaling exacerbated pancreatic inflammation and neoplasia. Therefore, beyond direct epithelial effects, sympathetic nerves promote pancreatitis and PDAC by co-opting myofibroblasts and myCAFs as disease amplifiers, highlighting CAF subtype-specific stromal interactions as putative therapeutic targets.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1337
bioRxiv. 2026 Feb 03. pii: 2026.02.03.703609. [Epub ahead of print]

Rapid optogenetic manipulation of autophagy reveals that the nuclear pore complex is a robust autophagy substrate.

Payel Mondal, Amanda Cyril, Louis Parham, Dana Mamriev, Igor Wierzbicki, Celina Shen, David J Gonzalez, Maximiliano A D'Angelo, Christina G Towers.

Autophagy, a conserved recycling process, manages intracellular quality control to mitigate stress. To determine the rapid effects of autophagy perturbation, we developed the first optogenetic tool to rapidly inhibit autophagy, termed ASAP. Our approach selectively inhibits autophagy within 5 minutes, providing a precise and dynamic approach to study autophagy regulation. Proteomic profiling with ASAP revealed the most tightly regulated autophagy substrates along with novel, previously unidentified substrates, including nuclear pore complex (NPC) proteins. Interestingly, autophagy regulates quality control of incomplete NPCs still in the cytoplasm via specific LC3-interacting regions (LIRs), sparing NPCs embedded in the nuclear envelope. Upon rapid autophagy inhibition, incomplete NPCs accumulate and instead of undergoing autophagic degradation, cytoplasmic NPCs aggregate in processing bodies. Using ASAP, we demonstrate rapid and specific inhibition of autophagy, revealing that the nuclear pore complex is a tightly regulated autophagy substrate.

DOI: https://doi.org/10.64898/2026.02.03.703609
J Exp Biol. 2026 Feb 11. pii: jeb.251083. [Epub ahead of print]

Physical activity and metabolic rates in humans.

Daniel E Lieberman, Andrew K Yegian, Steven B Heymsfield.

  All animals perform physical activity, but humans engage in a special kind of physical activity - exercise, defined as discretionary physical activity for health and fitness. However, the effects of physical activity on whole-organism metabolism and health are unresolved, partly because it is difficult to measure the three major components of metabolism: active energy expenditure (AEE), resting energy expenditure (REE) and dietary induced thermogenesis (DIT), which together equal total energy expenditure (TEE). Three competing models make different predictions about the effects of AEE on REE and TEE. Whereas the traditional 'additive' model of energy balance predicts that AEE is independent of REE, the 'stress' model hypothesizes that AEE temporarily increases REE partly because of transient effects of excess post-exercise oxygen consumption (EPOC). In contrast, the 'constrained energy' model predicts that increases in AEE cause compensatory decreases in REE to maintain a constant TEE. Here, we discuss how different analytical models, measurements, experimental designs and statistical methods affect tests of these three models' hypotheses. After accounting for spurious correlations, we find that longitudinal and cross-sectional data provide most support for the additive model. However, more and better data are needed to test these hypotheses rigorously. To conclude, we also review the evidence, mostly from humans, that increased levels of physical activity slow aging and reduce vulnerability to disease by diverting energy away from processes that improve reproductive success at the expense of long-term health and by increasing energy allocation to repair, maintenance and capacity-building.

Keywords:  Excess post-exercise oxygen consumption; Exercise; Health; Lifespan; Metabolism; Physical activity

DOI:  https://doi.org/10.1242/jeb.251083
bioRxiv. 2026 Feb 03. pii: 2026.02.01.703134. [Epub ahead of print]

ImmunoPheno: A Computational Framework for Data-Driven Design and Analysis of Immunophenotyping Experiments.

Lincoln Wu, Minh A Nguyen, Zhangliang Yang, Sriya Potluri, Shamilene Sivagnanam, Nell Kirchberger, Apoorva Joshi, Kyung J Ahn, Joseph S Tumulty, Emylette Cruz Cabrera, Neil Romberg, Kai Tan, Lisa M Coussens, Pablo G Camara.

Immunophenotyping is fundamental to characterizing tissue cellular composition, pathogenic processes, and immune infiltration, yet its accuracy and reproducibility remain constrained by heuristic antibody panel design and manual gating. Here, we present ImmunoPheno, an open-source computational platform that repurposes large-scale single-cell proteo-transcriptomic data to guide immunophenotyping experimental design and analysis. ImmunoPheno integrates existing datasets to automate the design of optimal antibody panels, gating strategies, and cell identity annotation. We used ImmunoPheno to construct a harmonized reference (HICAR) comprising 390 monoclonal antibodies and 93 human immune cell populations. Leveraging this resource, we algorithmically designed minimal panels to isolate rare populations, such as MAIT cells and pDCs, which we validated experimentally. We further demonstrate accurate cell identity annotation across publicly available and newly generated cytometry datasets spanning diverse technologies, including spatial platforms like CODEX. ImmunoPheno complements expert curation and supports continual expansion, providing a scalable framework to enhance the accuracy, reproducibility, and resolution of immunophenotyping.

DOI: https://doi.org/10.64898/2026.02.01.703134
Gut. 2026 Feb 09. pii: gutjnl-2025-336323. [Epub ahead of print]

MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.

Yang Chen, Gao-Wei Jin, Li-Hong He, Yu Dong, Yan-Na Zhang, Han-Xiang Guo, Yi-Ting Xu, Zi-Yang Wei, Bin-Fei Dang, Chun-Yang Mu, Wan-Yue Cao, Yi-Ze Zhang, Xiao-Bao Wei, Yu-Xiong Feng, Yun-Hua Liu, Qi Zhang, Ting-Bo Liang.

   BACKGROUND: Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.
OBJECTIVE: To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.
DESIGN: Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.
RESULTS: We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8+ T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.
CONCLUSION: Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.

Keywords:  CANCER IMMUNOBIOLOGY; LIVER METASTASES; OXIDATIVE METABOLISM; PANCREATIC CANCER

DOI:  https://doi.org/10.1136/gutjnl-2025-336323
Mol Cancer. 2026 Feb 10.

CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1.

Masahiro Maeda, Kenna Sherman, Weiqiang Zhou, Jiaqi Cheng, Yuta Nihongaki, Adrian Idrizi, Rakel Tryggvadottir, Oscar Camacho, Xingbo Shang, Jimin Min, Michael A Koldobskiy, Anirban Maitra, Andre Levchenko, Barbara S Slusher, Hongkai Ji, Andrew P Feinberg.

DOI: https://doi.org/10.1186/s12943-026-02575-z
United European Gastroenterol J. 2026 Feb;14(1): e70185

International Multidisciplinary Consensus Report on Definitions, Diagnostic Criteria, and Management of Fatty Pancreas: A Joint Statement Endorsed by EPC, APA, EASD, EASL, ESGAR, ESGE, ESP, ESPCG, ESPEN, ESPGHAN, IAP, JPS, KPBA, LAPSG, and UEG.

Miroslav Vujasinovic, Ihsan Ekin Demir, Giovanni Marchegiani, Peter Hegyi, Livia Archibugi, Roberto Valente, Gabriele Capurso, Heiko Witt, Stefanos Bonovas, Daniele Piovani, Jonas Rosendahl, Patrick Maisonneuve, Caroline S Verbeke, Muşturay Karçaaltıncaba, J Enrique Dominguez-Muñoz, Isabelle Scheers, Laszlo Czako, Robert Wagner, Vinciane Rebours, Daniel Öhlund, Ilkay S Idilman, Kasper Overbeek, Natalya Gubergrits, Trond Engjom, Albrecht Neesse, Minoti Apte, Mihailo Bezmarević, Rickmer Braren, Stefania Bunduc, Güralp Onur Ceyhan, Manil Dinesh Chouhan, Anne Couvelard, Jérôme Cros, Daniel de la Iglesia, Enrique de-Madaria, Joost P H Drenth, Asbjørn Mohr Drewes, Arantza Fariña Sarasqueta, Pierluigi Fracasso, Sven Francque, Jens Brøndum Frøkjær, Julio Iglesias-Garcia, Pramod Garg, Felicia Gerst, Antanas Gulbinas, Ibrahim Halil Gürcinar, Martin Heni, Jong Jin Hyun, Eduard Jonas, Mariia Kiriukova, Masayuki Kitano, Aleksander Krag, Johanna Laukkarinen, Mónika Lipp, Martin Lovecek, Marc Martignoni, Etna Masip, Ryotaro Matsumoto, Anders Molven, Tetiana Mozhyna, Lenka Nosakova, Verena Obmann, Johann Ockenga, Sanjay Pandanaboyana, Nikola Panić, Georgios Papachristou, Analia Verónica Pasqua, Katarzyna M Pawlak, Mario Pelaez-Luna, Ivonne Regel, Sara Regnér, Stuart Robinson, Andrada Seicean, Vijay Singh, Mark M Smits, Min Je Sung, Matteo Tacelli, Roy Taylor, Brigitta Teutsch, Mihaela Udrescu, Michael Wilschanski, Aslihan Yavas, Giulia A Zamboni, J Matthias Löhr.

  This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt "fatty pancreas" as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta-cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high-quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence-based clinical practice in this emerging field.

Keywords:  acute pancreatitis; beta‐cell; chronic pancreatitis; diabetes mellitus; fatty; intraductal papillary mucinous neoplasms; metabolic syndrome; pancreas; pancreatic cancer; pancreatic exocrine insufficiency

DOI:  https://doi.org/10.1002/ueg2.70185
J Mol Biol. 2026 Feb 06. pii: S0022-2836(26)00054-9. [Epub ahead of print] 169681

CLISGen: A Comprehensive Resource of SNP Genotypes for Human Cell Lines.

Matteo Marchesin, Davide Dalfovo, Alessandro Romanel.

  Selecting cell lines with specific Single Nucleotide Polymorphism (SNP) genotypes is a critical bottleneck in functional genomics, often requiring advanced bioinformatic skills. To address this, we developed CLISGen (Cell Lines SNP Genotypes), a database with a user-friendly web application that simplifies access to SNP genotypes in over 1,000 cancer cell lines from the Cancer Cell Line Encyclopedia. CLISGen integrates and harmonizes data from Whole-Genome, Whole-Exome, and RNA sequencing, enriching it with contextual information like copy number alterations and genetic ancestry. The platform allows users to search for specific variants or variants in specific genes or genomic regions and filter results by tissue type or data quality, providing intuitive graphical and tabular outputs. By eliminating a major experimental bottleneck, CLISGen offers researchers a powerful resource to efficiently select suitable cell models for studying the link between genetic variation and cancer. CLISGen is freely available at https://bcglab.cibio.unitn.it/clisgen.

Keywords:  Cancer cell lines; Database; Functional genomics; Genotyping; Single nucleotide polymorphism (SNP)

DOI:  https://doi.org/10.1016/j.jmb.2026.169681
Cell. 2026 Feb 11. pii: S0092-8674(25)01491-6. [Epub ahead of print]

CLIM-TIME identifies metastatic microenvironment modulators for T cell therapy response.

Yinghua Wang, Weiwei Hu, Rui Xia, Xianfa Yang, Yange Gu, Zihan Ning, Tiange Yang, Chune Yu, Lulu Zhang, Dun Li, Yitian Jin, Jianhua Li, Feifei Zhang, Yaochen Xu, Chenqi Xu, Zhengxin Wang, Naihe Jing, Luonan Chen, Guangchuan Wang.

  The tumor microenvironment (TME) poses a major barrier to effective immunotherapy, yet high-throughput perturbation-mapping approaches to dissect TME spatial complexity and its contextual immune modulators remain lacking. Here, we introduce CRISPR-laser-captured microdissection (LCM) integration mapping of the tumor-immune microenvironment (CLIM-TIME), a scalable platform that integrates CRISPR screening with LCM of metastatic tumors for transcriptomic, deconvolution, and immunofluorescence analyses. CLIM-TIME enables spatially resolved mapping of how tumor suppressor gene (TSG) loss reshapes the TME and modulates immune responses. We identified seven distinct TME subtypes, revealing that DNA repair and Polycomb repressive complex (PRC) TSG loss is linked to immune-infiltrated TMEs sensitive to T cell therapy. In contrast, knockouts of TSGs in the Hippo pathway promoted immune evasion and therapy resistance by fostering myeloid-enriched but T cell-excluded TMEs with elevated extracellular matrix (ECM). Targeting the ECM-crosslinking enzyme LOXL2 effectively remodeled the metastatic TME, enhancing T cell infiltration and improving therapeutic efficacy in lung metastases across multiple cancers.

Keywords:  Hippo pathway; LOXL2; T cell infiltration; T cell therapy; extracellular matrix; immunotherapy; metastasis; spatial CRISPR; tumor microenvironment; tumor suppressor gene

DOI:  https://doi.org/10.1016/j.cell.2025.12.042
bioRxiv. 2026 Jan 29. pii: 2026.01.27.702014. [Epub ahead of print]

Distinct control of T cell proliferation and effector function by partitioning of intracellular sulfur from cysteine.

Beth Kelly, Minsun Cha, Tatjana Gremelspacher, Jacob L Martin, Massimo Andreis, Gustavo E Carrizo, Mia Gidley, Michal A Stanczak, Petya Apostolova, David E Sanin, Ananya Majumdar, Erika L Pearce.

Delineating how acquired nutrients are partitioned into different intracellular pathways, and how these various fates support distinct functions in T cells is limited. We show that CD8 + T cells acquire cysteine to serve both as a substrate for glutathione (GSH) production, which modulates effector functions, and to cede its sulfur for NFS1-dependent FeS-cluster synthesis, which supports proliferation. NFS1 deletion in activated CD8 + T cells promotes exhaustion and dampens anti-cancer immunity, while blocking cysteine flux into GSH, or enforcing FeS metabolism, enhance tumor control. This role for disrupted FeS metabolism in T cell exhaustion is echoed in data from human HCC. Elucidating how different intracellular pathways use cysteine enables targeted control of cysteine flux to retain beneficial effects of cysteine while abolishing those that restrain function. We illustrate this concept for one metabolite, cysteine, but it is likely to apply to other metabolites relevant for immune cell function.

DOI: https://doi.org/10.64898/2026.01.27.702014
Adv Sci (Weinh). 2026 Feb 09. e16847

Cohort-Scale Spatial Autocorrelation for Tumor Prediction in Mid-Infrared Pathology and Spatial Biomarker Discovery Using MALDI Imaging Lipidomics.

Miriam F Rittel, Nikolas Ebert, Denis Abu Sammour, Sebastian Graf, Björn C Fröhlich, Emrullah Birgin, Shad A Mohammed, Nuh N Rahbari, Axel Wellmann, Oliver Wasenmüller, Cleo-Aron Weis, Stefan Schmidt, Carsten Hopf.

  Mid-infrared (MIR) imaging is an emerging label-free modality for classifying tissue types, including viable tumor in highly heterogeneous cancers, by assessing spatial differences in chemical composition. However, common data analysis neglects spatial vicinity and relies on time-consuming pathological insight for hotspot prediction of viable tumor areas and computational tissue type annotation. Here, we present a method that uses spatial autocorrelation on MIR projection images computed from data of selected wavenumbers found by random forest ranking for computational tissue type annotation: Interdependent data processing enabled high accuracy annotations, whereas referencing of sequentially added new samples to a hyperspectral tissue database ensured computational efficiency and scalability for larger cohorts. Applied to clinical colorectal cancer liver metastasis samples, the method matched manual pathology assessment in a double-blind study. As an option, MIR-based hotspots can be correlated with mass spectrometry imaging. This multimodal approach identified sphingomyelin isoforms as lipidomic tumor marker candidates by imaging parallel reaction monitoring-parallel accumulation serial fragmentation (iprm-PASEF) directly on tissue. Taken together, spatial autocorrelation analysis on MIR imaging data could improve automated accurate annotation of tissue morphologies of heterogeneous cancer specimens and support the discovery of spatial cancer biomarkers.

Keywords:  MALDI imaging; colorectal cancer liver metastasis; mass spectrometry imaging; mid‐infrared imaging; multimodal correlative imaging; spatial autocorrelation

DOI:  https://doi.org/10.1002/advs.202516847
J Invest Dermatol. 2026 Feb 10. pii: S0022-202X(26)00016-3. [Epub ahead of print]

Monitoring senescent cell dynamics in wound healing using a p16-tdtomato mouse model.

Qiaoling Wang, Maria Shvedova, Magda Abdelkader, Daniel S Roh.

  Although accumulating evidence implicates cellular senescence in acute wound healing, the precise roles of senescent cells within distinct cell lineages during this process remain elusive. To address this, we employed the p16-tdTomato reporter mouse model for labeling and isolating senescent cells from wound tissue. Longitudinal in vivo imaging monitoring revealed the temporal dynamics of tdTomato (tdTom) fluorescence, with signal detection as early as postoperative day 3, peaking by day 6. Utilizing an optimized tissue digestion protocol, we achieved high-viability FACS isolation of p16INK4a-expressing cells (tdTom+), which exhibited characteristic senescent cell morphology and marker expression. Single-cell analysis demonstrated that tdTom+ wound cells enriched with p16 expression were primarily characterized as fibroblasts and displayed common features of senescence. These findings validate the p16-tdTomato reporter mouse as a reliable model for identifying and isolating senescent cells from the wound microenvironment at single-cell resolution.

Keywords:  Cellular senescence; Methods and techniques for skin research; Mouse model; Wound healing; p16; tdTomato

DOI:  https://doi.org/10.1016/j.jid.2025.12.029
bioRxiv. 2026 Feb 03. pii: 2026.02.01.703113. [Epub ahead of print]

SLC33A1 exports oxidized glutathione to maintain endoplasmic reticulum redox homeostasis.

Shanshan Liu, Mark Gad, Caifan Li, Kevin Cho, Yuyang Liu, Khando Wangdu, Viktor Belay, Alon Millet, Hiroyuki Kojima, Henry Sanford, Michele Wölk, Linas Urnavicius, Maria Fedorova, Gary J Patti, Ekaterina V Vinogradova, Richard K Hite, Kıvanç Birsoy.

The endoplasmic reticulum (ER) requires an oxidative environment to support the efficient maturation of secretory and membrane proteins. This is in part established by glutathione, a redox-active metabolite present in reduced (GSH) and oxidized (GSSG) forms. The ER maintains a higher GSSG:GSH ratio than the cytosol; however, the mechanisms controlling ER redox balance remain poorly understood. To address this, we developed a method for the rapid immunopurification of the ER, enabling comprehensive profiling of its proteome and metabolome. Combining this approach with CRISPR screening, we identified SLC33A1 as the major ER GSSG exporter in mammalian cells. Loss of SLC33A1 leads to GSSG accumulation in the ER and a liposome-based assay demonstrates that SLC33A1 directly transports GSSG. Cryo-EM structures and molecular dynamics simulations reveal how SLC33A1 binds GSSG and identify residues critical for its transport. Finally, an imbalance in GSSG:GSH ratio induces ER stress and dependency on the ER-associated degradation (ERAD) pathway, driven by a shift in protein disulfide isomerases (PDIs) toward their oxidized forms. Altogether, our work establishes SLC33A1-mediated GSSG export as a key mechanism for ER redox homeostasis and protein maturation.

DOI: https://doi.org/10.64898/2026.02.01.703113
Gut. 2026 Feb 10. pii: gutjnl-2025-337606. [Epub ahead of print]

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

Guan-Feng Gao, Zhao-Hui Ruan, Shi-Bo Zhang, Shuai He, Yi-Qi Li, Jin-Li Lyu, Yang Liu, Xing-Liang Tan, Yan-Jun Wang, Zhuo-Wei Liu, Guang-Zhao Lv, Gong Chen, Jie-Hai Yu, Pan-Pan Wei, Jian-Fu Zhao, Zhi-Ting Sun, Zheng Zhao, Yu Shi, Wei Liao, Shu-Wei Chen, Nu Zhang, Dong-Ming Kuang, Xin-Yuan Guan, Rou-Jun Peng, Mu-Yan Cai, Kai Yao, Xiu-Wu Bian, Pei-Rong Ding, Chun-Ling Luo, Jin-Xin Bei.

   BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear.
OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME.
DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways.
RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis.
CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Keywords:  CANCER; CELL MIGRATION; COLORECTAL METASTASES

DOI:  https://doi.org/10.1136/gutjnl-2025-337606
Autophagy Rep. 2026 ;5(1): 2622228

Autophagy in kidney physiology: from cellular quality control to organ metabolism.

Takeshi Yamamoto, Satoshi Minami, Yoshitaka Isaka.

  Autophagy is a cellular process that maintains kidney physiology by recycling intracellular components to preserve homeostasis. In the kidney, autophagy supports energy metabolism and integrity across multiple cell types. Its regulation is tightly governed by nutrient availability, hormonal cues, and oxygen levels, primarily through signaling pathways such as mechanistic target of rapamycin kinase (mTOR), AMP-activated protein kinase (AMPK), and transcription factor EB (TFEB). Under physiological conditions, autophagy is dynamically regulated to meet metabolic demands. However, aging, obesity, and metabolic stress impair lysosomal function, leading to a pathological state termed autophagic stagnation, in which autophagosomes accumulate but degradative flux is compromised. Rather than being uniformly protective, this stagnation promotes cellular damage and contributes to kidney disease progression. Notably, autophagic stagnation in proximal tubular epithelial cells (PTECs) contributes to acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition and exacerbates lipotoxicity in obesity-related kidney disease. Recent studies highlight the importance of transcriptional regulators - including TFEB and MondoA - in maintaining autophagic activity and mitochondrial homeostasis. Therapeutic strategies aimed at restoring autophagic flux - pharmacologically or through lifestyle interventions such as caloric restriction - hold promise for preserving kidney function. Deeper understanding of cell type - specific autophagy regulation will be critical for developing targeted and context-specific therapies.

Keywords:  Mitophagy; Rubicon; autophagic stagnation; fibroblast growth factor 21 (FGF21); lipophagy; lysophagy; proximal tubular epithelial cells (PTECs)

DOI:  https://doi.org/10.1080/27694127.2026.2622228
bioRxiv. 2026 Feb 02. pii: 2025.07.19.665650. [Epub ahead of print]

AutoMorphoTrack: A modular framework for quantitative analysis of organelle morphology, motility, and interactions at single-cell resolution.

Armin Bayati, Jackson G Schumacher, Xiqun Chen.

Quantitative imaging of organelle dynamics provides crucial insights into cellular function, state, and organization; however, existing analysis workflows often require advanced coding expertise and multiple software tools. AutoMorphoTrack is an open-source Python toolkit that automates organelle detection, morphology classification, motility tracking, and colocalization from multichannel fluorescence microscopy image stacks. The platform includes adaptive segmentation, organelle trajectory reconstruction, and pixel-level overlap quantification within a unified, reproducible framework that can be executed as an interactive Jupyter notebook, a modular Python package, or through AI-assisted natural-language commands. Each analysis step outputs publication-ready images, time-lapse videos, and standardized quantitative data tables. To complement the main pipeline, an accompanying script-AMTComparison.py-is provided to demonstrate how AutoMorphoTrack's outputs can be extended for comparative analysis across individual neurons or experimental conditions. Together, these tools provide an accessible and framework for high-content, reproducible quantification of subcellular morphology, motility, and interactions at single-cell resolution.

DOI: https://doi.org/10.1101/2025.07.19.665650
Adv Sci (Weinh). 2026 Feb 10. e16859

β-Adrenergic Signaling Promotes Anti-Tumor Immunity in TP53-mutant Oral Squamous Cell Carcinoma.

Frederico O Gleber-Netto, Deborah Silverman, Tongxin Xie, Shamima Akhter, Nicole R Vaughn, Adewale Adebayo, Kala Chand Debnath, Shorook Naara, Shajedul Islam, Erik Knutsen, Emily Lorin Ashkin, Simone Anfossi, Sara Leahey, Patrick Hwu, Sebastien Talbot, Erica K Sloan, Robert Saddawi-Konefka, Roberto Rangel, Jeffrey N Myers, George A Calin, Moran Amit.

  Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to immunotherapy. The interplay between β-adrenergic signaling and p53 loss, both key regulators of immune responses, has remained largely unexplored in the setting of tumor-immune evasion. This study demonstrates that pharmacologic stimulation of β2-adrenergic receptors with isoprenaline significantly enhances cytotoxic T cell activity against p53-deficient HNSCC cells via a CXCL10-dependent paracrine mechanism. Comprehensive transcriptomic and co-culture assays reveal that p53-null cancer cells upregulate CXCL10, which promotes CD8+ T cell recruitment and activation. Neutralization of CXCL10 abolishes the β-adrenergic-induced cytotoxic T cell response, establishing this chemokine as a pivotal mediator. Using tyrosine hydroxylase knockout mouse models, we show that adrenergic innervation is essential for intra-tumoral CXCL10 expression and the infiltration of effector CXCR3+ T cells in vivo. Notably, the CXCL10-driven T cell response is associated with simultaneous upregulation of both activation and exhaustion markers, indicating a robust but transient effector state within the tumor microenvironment. Collectively, these findings uncover a neuro-immune axis that reverses immune escape in p53-deficient HNSCC and suggest novel therapeutic strategies targeting adrenergic signaling to convert immune "cold" tumors into "hot" ones more amenable to immunotherapy.

Keywords:  CXCL10; head and neck cancer; neuroscience; β‐adrenergic signaling

DOI:  https://doi.org/10.1002/advs.202516859
bioRxiv. 2026 Feb 04. pii: 2026.02.02.703178. [Epub ahead of print]

The aging mouse lipidome.

Edgar Esparza, Steven E Pilley, Xuanyi Shi, Preeti Iyengar, Shruti Sivaraman, George Wang, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Aeowynn J Coakley, Ryo Higuchi-Sanabria, Whitaker Cohn, Peter J Mullen.

Aging is associated with widespread metabolic changes that contribute to functional decline and disease. While prior studies have characterized age-associated changes in lipids, it still remains incompletely understood how the lipidome changes across tissues and between sexes during aging. Here, we performed targeted lipidomics across 10 organs collected from male and female mice at five ages spanning adolescence to old age. We analyzed 775 lipids across multiple lipid classes and found that aging affects the lipidome in an organ-specific manner. The thymus and quadriceps muscle had the most age-associated lipid changes, whereas lipid levels in organs such as the kidney and lung remained more stable. In quadriceps muscle, aging was associated with a decrease in specific phosphatidylcholine and phosphatidylethanolamine lipids, particularly those containing adrenic acid. We also identified sex-dependent differences in lipid composition, with the spleen showing differences throughout life. Spleens from female mice had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine compared to males. Together, these data provide a comprehensive atlas of age- and sex-associated lipid changes across mouse organs and complement existing metabolic and transcriptomic resources to support studies of mouse aging.

DOI: https://doi.org/10.64898/2026.02.02.703178
Nat Commun. 2026 Feb 11.

Negative feedback regulation of STING signaling by TAX1BP1-directed Golgiphagy.

Sujit Suklabaidya, Suchitra Mohanty, Irene E Reider, Jesse White, Dominic Colter, Sarah M McCormick, Noula Shembade, Young Bong Choi, Christopher C Norbury, Edward W Harhaj.

The cGAS-STING pathway is a critical regulator of type I Interferon (IFN) and inflammation upon cytosolic DNA-sensing. cGAS-STING signaling termination is regulated by lysosomal-mediated degradation of STING; however, the mechanisms controlling the inhibitory targeting of STING are incompletely understood. Here, we identify the selective autophagy receptor TAX1BP1 as a negative regulator of the cGAS-STING pathway. TAX1BP1-deficient macrophages activated by cGAS or STING agonists accumulate higher-order STING aggregates, exhibit heightened STING signaling, and increased production of type I IFN and proinflammatory cytokines. Mechanistically, TAX1BP1 promotes STING degradation through microautophagy by facilitating the interaction of STING with the ESCRT-0 protein HGS. Furthermore, STING activation is associated with the swelling and fragmentation of the Golgi apparatus, and TAX1BP1 and p62/SQSTM1 are essential for the autophagic degradation of fragmented Golgi (Golgiphagy). Our findings suggest that STING activation at the Golgi is coupled to its downregulation by Golgiphagy to restrict innate immune responses.

DOI: https://doi.org/10.1038/s41467-026-69422-z
ESMO Open. 2026 Feb 12. pii: S2059-7029(25)01913-1. [Epub ahead of print]11(3): 106043

NALIRIFOX versus nab-paclitaxel and gemcitabine in older patients with treatment-naive metastatic pancreatic cancer: a subgroup analysis of the pivotal NAPOLI 3 trial.

T Macarulla, R Pazo Cid, M S Womack, A Cubillo Gracian, A Zervoudakis, H Hatoum, V Chung, A Patel, A S Paulson, S Pant, E M O'Reilly, R A Hubner, E Van Cutsem, T Bekaii-Saab, L Zhang, J Li, H Chen, F Maxwell, Z A Wainberg, D Melisi.

   BACKGROUND: The phase III NAPOLI 3 trial established liposomal irinotecan in combination with 5-fluorouracil/leucovorin plus oxaliplatin (NALIRIFOX) as a superior first-line (1L) treatment option compared with gemcitabine plus nab-paclitaxel (Gem + NabP) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), without imposing an upper age limit on enrollment. The current analysis of the NAPOLI 3 data investigated the potential impact of older age on the efficacy and safety of NALIRIFOX.
PATIENTS AND METHODS: Adults with previously untreated mPDAC were randomly assigned in a 1 : 1 ratio to receive NALIRIFOX or Gem + NabP. This post hoc analysis compared outcomes for patients aged ≥70 years versus <70 years. Endpoints included overall survival (OS), progression-free survival (PFS), and safety. No statistical comparison was carried out.
RESULTS: Of the 770 patients in the NAPOLI 3 population, 553 were aged <70 years and 217 were aged ≥70 years. Median OS and median PFS with NALIRIFOX were 11.7 months and 7.4 months, respectively, in the <70 years subgroup (n = 275) and 10.0 months and 7.3 months, respectively, in the ≥70 years subgroup (n = 108). The benefit of NALIRIFOX versus Gem + NabP was preserved in the older versus younger subgroup. There was no evidence of increased treatment-related toxicity in the older (versus younger) subgroup.
CONCLUSIONS: NALIRIFOX improved mPDAC survival versus Gem + NabP irrespective of patient age, with no signals for reduced tolerability in the older (versus younger) patients. The results provide reassurance that triplet therapy with NALIRIFOX is an efficacious and tolerable regimen in older treatment-naive patients with mPDAC who were fit enough for inclusion in NAPOLI 3, supporting consideration of its use as 1L therapy in this population.

Keywords:  NALIRIFOX; NAPOLI 3; age; liposomal irinotecan; mPDAC; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.esmoop.2025.106043
J Chem Phys. 2026 Feb 14. pii: 064907. [Epub ahead of print]164(6):

Molecular origins of viscoelasticity in biomolecular condensates.

Pablo L Garcia, Jerelle A Joseph.

Biomolecular condensates are membraneless organelles that compartmentalize functions in living cells. Formed by the phase separation of biomolecules, condensates possess a wide range of mechanical responses. However, how condensate viscoelastic response is encoded in the chemistries of their constituents-such as intrinsically disordered proteins (IDPs)-is not well understood. Here, we employ molecular dynamics simulations to connect measurable condensate viscoelasticity to the architectural heterogeneity and dynamic reconfigurability of associative networks formed by IDPs. Using a residue-resolution coarse-grained model, we characterize biologically relevant and synthetic condensates, demonstrating that the temperature sensitivity of elasticity is sequence-dependent and modeled by exponential scaling laws. We interrogate condensate mesh heterogeneity via entanglement spacing, finding that entropy-driven structural heterogeneity and reduced IDP hydrophobicity favor condensate elasticity. Furthermore, we construct graph-theoretical representations of condensates and find that interaction network topologies with an abundance of redundant node pathways translate to more load-bearing paths for mechanical stress storage. Strikingly, we discover that elastic coupling of IDPs within condensates emerges when single-molecule shape memory timescales approach mesh reconfiguration timescales. This interplay of timescales for molecular and microstructural processes, which we introduce as the condensate Deborah number, dictates how restoring elastic forces propagate and are stored across IDP networks, linking condensate microstructure dynamics directly to mechanical responses. Taken together, our work provides a conceptual framework of how condensates act as stress-responsive biomaterials, helping illuminate how cells exploit condensate mechanics to sense and regulate their internal environment and opening avenues for the design of condensates with programmable viscoelastic properties.

DOI: https://doi.org/10.1063/5.0309619