bims-cagime 2026-09-27 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–09–27
39 papers selected by
Kıvanç Görgülü, Technical University of Munich

Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.
Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer.
Metastatic pancreatic cancer: from human disease to preclinical modelling.
Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.
Metastatic niche shaped by host factors influences disseminated cancer cell fate.
Current Landscape of RAS-Targeted Therapy for Pancreatic Cancer.
Conserved Metastatic Cell States and Spatial Immune Microenvironment Remodeling Define Pancreatic Cancer Liver Metastases.
An iron-regulated methionine redox axis governs adipose browning and cancer cachexia.
Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.
Targeting RAS for Pancreatic Cancer Interception.
Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles.
Mammals produce cyclo-octasulfur to suppress lipid peroxidation and ferroptosis.
Niche-Specific Stromal Crosstalk in PDAC Liver Metastasis.
From blunt-force treatment to precision: 25 years of transformation in cancer research.
Reassessing the Role of Progenitor Cells in Muscle Wasting in Cancer Cachexia.
RamanOmics decodes the spatial vibrational-molecular architecture of senescence in aging and repair.
Longitudinal Analysis of Matched Patient Biospecimens Reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Cancer.
Inflammatory memory inactivates AMPK-stimulated DDR1 degradation to enable pancreatic cancer growth.
Resident tissue macrophages transfer selenium transporter protein to protect pancreatic cancer from ferroptosis.
Cell death: immunogenic potential of cuproptosis in cancer.
TRPML1 loss disrupts lysosome-mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy.
LC3 forms functional nanoclusters on autophagosomes.
Cancer Neuroscience: Establishing a home in Neuro-Oncology.
In situ visualization of autophagy reveals the presence of vesicles at the expanding phagophore rim.
Load-dependent RGD-context sensing via αV-class integrins reprograms cell adhesion and mechanics.
A quantitative redox proteome of the human muscle response to exercise.
Cell-intrinsic functions of PD-L1 activate autophagy and prevent cytokine-induced apoptosis.
A Phase I Study of Nab-Paclitaxel, Gemcitabine and AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas: ECOG-ACRIN EA2131.
Differential lipid selectivity of StARD phospholipid transporters revealed by native MS.
Enhanced Ratiometric Indicators for (Sub)cellular Detection of Magnesium(II) Ions by Flow Cytometry.
Role of PRMT5 in regulating ferritinophagy during Mycobacterium tuberculosis infection.
Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.
Positive selection screen identifies natural product β-catenin inactivators.
Melanoma evolution in the lymph node shapes systemic outcomes.
ATG8 protein clustering: a HOTS topic in autophagy.
The mechanisms and mechanics of aging.
Multi-Modal Kinome Profiling Discovers Mesenchymal-Like Polarity Networks that Underly Directed Hepatocellular Carcinoma Cell Migration.

Nature. 2026 Sep 23.

Hepatocytes promote liver metastasis of pancreatic cancer by providing serine.

Koelina Ganguly, Keisuke Yamamoto, Jason Rodencal, Joel Encarnacion-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Ruohong Wang, Carolina Alcantara Hirsch, Anthony Sorrentino, Elshaddai Z White, Paul M Grandgenett, Michael A Hollingsworth, Miwako Kakiuchi, Richard Possemato, Dafna Bar-Sagi, Mitsuhiro Fujishiro, Alec C Kimmelman.

The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3-5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron-tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5-CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K-AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5-CXCR2-PI3K-AKT-FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell-hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.

DOI: https://doi.org/10.1038/s41586-026-11051-z
Science. 2026 Sep 24. 393(6818): eaeg4791

Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.

Clemens Hinterleitner, Valentin J A Barthet, Hailey V Goldberg, Kristen C Vogt, Ana Marie Perea, Logan R Hillger, Stephen Ruiz, Domhnall McHugh, Yu-Jui Ho, Almudena Chaves-Perez, Maria Skamagki, Sara Flowers, Hannah C Styers, Natasha Rekhtman, Xueqian Zhuang, Gabriel Dessotti Barretto, Xiang Li, Jadae T Watson, Wei Luan, Janelle Simon, Tuomas Tammela, Rui Gardner, Charles M Rudin, Paul B Romesser, Matthew J Bott, Aveline Filliol, Daniel A Heller, Scott W Lowe.

Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

DOI: https://doi.org/10.1126/science.aeg4791
Cell. 2026 Sep 23. pii: S0092-8674(26)01018-4. [Epub ahead of print]

CD4 T cells convert transient responses to KRAS inhibition to durable remissions in pancreatic cancer.

Li Qiang, Megan T Hoffman, Jung-Ho Chun, Brendan Parent, Felix Hambitzer, Frank Peprah, Courtney T S Kureshi, Birkley S Lim, Eugena Chang, Michael J Walsh, Julissa G Tello, Tavus Atajanova, Hojeong Shin, Corey Perkins, Rakeeb Kureshi, Yaniris Molina-Aponte, James M Dougan, Chong Zuo, Lauren Brais, Thomas E Clancy, James M Cleary, Jason L Hornick, Brandon M Huffman, Joseph D Mancias, George Molina, Mark Fairweather, Jonathan A Nowak, Kimberly J Perez, Douglas A Rubinson, Sarah Slater, Ritchell van Dams, Jiping Wang, Brian M Wolpin, Kwok-Kin Wong, Harshabad Singh, Andrew J Aguirre, David Baker, Michael Dougan, Stephanie K Dougan.

  Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon γ (IFN-γ), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-γ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.

Keywords:  CD4 T cells; IL-21; KRAS; MRTX1133; Th1 cells; cDC2; cytokines; daraxonrasib; designed proteins; immunotherapy; pancreatic cancer

DOI:  https://doi.org/10.1016/j.cell.2026.08.045
Gut. 2026 Sep 24. pii: gutjnl-2025-336334. [Epub ahead of print]

Metastatic pancreatic cancer: from human disease to preclinical modelling.

Jimin Min, Vasiliki Liaki, Peter Y Yu, Carmen Guerra, Anirban Maitra.

  Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid cancers, portending poor patient outcomes due to challenges in precise diagnosis and therapeutic resistance. Extensive molecular heterogeneity of metastatic tumours and their frequent evasion from clinical detection represent critical bottlenecks in disease management. Despite substantial research efforts, optimal clinical management remains an ongoing challenge. In this review, we outline the current understanding of metastatic pancreatic cancer, including its clinical features in patients. Emerging evidence highlights the pivotal roles of dynamic interactions between cancer cells and organ-specific and niche-specific microenvironments during metastatic spread. We further summarise the known molecular characteristics of metastatic PDAC and the preclinical models developed in pancreatic cancer research for functional interrogation. Finally, based on the current knowledge of this disease, we discuss existing limitations and future opportunities for advancing precision oncology approaches. These efforts may open promising avenues for the development of more effective clinical strategies aimed at mitigating metastasis in PDAC.

Keywords:  PANCREATIC CANCER

DOI:  https://doi.org/10.1136/gutjnl-2025-336334
J Physiol. 2026 Sep 24.

Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.

Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Sung Gi Noh, Martin Picard, Abbey-Gale Mannings, Michael S Cohen, Dennis W Wolan, Terence E Ryan, Russell T Hepple.

  Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations in mitochondrial morphology suggest that mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischaemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumour-conditioned media (TCM) could promote mPT and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in a breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibres increased mitochondrial reactive oxygen species (mROS) and caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion colocalization and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle-wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle-wasting disorders. KEY POINTS: Mitochondrial permeability transition (mPT) induces marked alterations in mitochondrial morphology and muscle phenotypes that are common in wasting conditions. mPT is promoted by tumour-derived factors in a manner that depends in part on the mPT-regulating protein CypD. mPT generates transcriptional alterations that overlap with cachectic muscle in a mouse model of pancreatic cancer, particularly during the period of muscle wasting. Pharmacological targeting of mPT attenuates or prevents atrophy in C2C12 and human primary myotubes, respectively.

Keywords:  mitochondrial permeability transition; mitophagy; muscle atrophy; muscle wasting; neuromuscular junction

DOI:  https://doi.org/10.1113/JP291213
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00034-1. [Epub ahead of print]406 1-42

Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.

Satoshi Minami, Maho Hamasaki.

  Lysosomes were once considered terminal degradative organelles responsible for disposing of cellular waste. However, recent studies have revealed that lysosomes serve as dynamic signalling and metabolic hubs at the center of diverse biological processes, including nutrient sensing, metabolic regulation, membrane trafficking, autophagy, inflammation, and cell death. To support this broad functional repertoire, lysosomes must possess robust mechanisms to maintain their integrity in the face of damage or stress. In response to lysosomal membrane damage, cells engage multilayered adaptive mechanisms that act in coordination-membrane repair (Repair), selective removal of damaged organelles (Removal), and de novo biogenesis of lysosomes (Regeneration). These processes are mediated by a range of molecular pathways, including the ESCRT complex, the PITT pathway, lysophagy, and TFEB-dependent lysosomal regeneration. Notably, recent findings highlight the noncanonical autophagy-like pathway known as ATG8ylation (conjugation of ATG8s on single membranes), which is activated via the STING-V-ATPase-ATG16L1 axis and functions as a critical hub connecting multiple arms of the lysosomal damage response. In this review, we systematically outline the molecular basis of lysosomal damage responses, including ATG8ylation, and explore how these networks are implicated in a broad spectrum of pathological conditions such as aging, neurodegeneration, cancer, obesity-related disorders, and immune dysfunction. Understanding these lysosomal quality control mechanisms not only sheds light on the fundamental principles of organelle homeostasis but also opens new avenues for therapeutic innovation.

Keywords:  Lysophagy; Lysosome; Organelle damage; Selective autophagy

DOI:  https://doi.org/10.1016/bs.ircmb.2026.04.002
FEBS Lett. 2026 Sep 21.

Metastatic niche shaped by host factors influences disseminated cancer cell fate.

Gwennan Delyth Ward, Álvaro Ruiz-Tabas, Patricia Altea-Manzano.

  Metastasis is responsible for the vast majority of cancer-related deaths, yet organ selectivity and the fate of disseminated cancer cells remain incompletely understood. While tumor-intrinsic programs have been extensively characterized, increasing evidence indicates that host-related extrinsic factors critically modulate the molecular and cellular landscape of metastatic niches. Aging, dietary habits, microbiome, physical activity, smoking, air pollution, and chronic stress may reshape systemic inflammation, immune surveillance, vascular permeability, stromal composition, extracellular matrix remodeling, and metabolic signaling in organs commonly targeted by metastasis, including bone, lung, liver, and brain. These host-dependent alterations influence disseminated cancer cell homing, extravasation, dormancy, and proliferative outgrowth by reprogramming tissue-resident and recruited cell populations, as well as niche-derived soluble and mechanical cues. In this review, we describe a framework in which metastasis is dynamically codetermined by tumor cell plasticity and host systemic state, contextualized by recent mechanistic insights into how lifestyle and physiological states rewire organ microenvironments to become either permissive or restrictive to metastatic colonization. Understanding these interactions may reveal actionable targets for metastasis prevention and highlight modifiable behaviors as biological determinants of organ susceptibility to metastatic disease.

Keywords:  Metastasis; aging; diet; host; immune system; lifestyle factors; metastatic niche; microbiome; systemic inflammation

DOI:  https://doi.org/10.1002/1873-3468.70471
Oncologist. 2026 Sep 23. pii: oyag379. [Epub ahead of print]

Current Landscape of RAS-Targeted Therapy for Pancreatic Cancer.

Y Linda Wu, Benjamin Herzberg, Gulam A Manji.

  Pancreatic ductal adenocarcinoma (PDAC) continues to carry a poor prognosis, and only incremental gains in systemic therapy have been made over the past decade. Because activating KRAS mutations are present in more than 90% of PDAC and serve as the inciting oncogenic driver, RAS has long been a coveted but elusive therapeutic target, historically deemed "undruggable." Allele-specific KRASG12C inhibitors provided the first proof of concept, but G12C mutations account for only about 1% of PDAC, in which G12D, G12V, and G12R predominate. Recent advances in the structural and biochemical understanding of RAS have yielded a rapidly expanding therapeutic landscape, broadly comprising non-G12C allele-specific inhibitors, pan-RAS and pan-KRAS inhibitors, and proteolysis-targeting chimeras. This progress is exemplified by the phase III RASolute-302 trial, in which the RAS(ON) multi-selective tri-complex inhibitor daraxonrasib nearly doubled overall survival versus chemotherapy in previously treated metastatic PDAC (13.2 vs 6.7 months), positioning it to become the first broadly applicable RAS-targeted therapy in this disease. Here we review the biology of RAS, the mechanistic rationale and clinical data behind emerging RAS-directed agents, and the central challenges ahead: targeting different KRAS subtypes, managing distinct toxicities, and overcoming the genetic and non-genetic resistance mechanisms that will require rational combination strategies to translate these gains into durable benefit.

Keywords:  KRAS; RAS inhibitors; daraxonrasib; pancreas cancer; targeted therapy

DOI:  https://doi.org/10.1093/oncolo/oyag379
bioRxiv. 2026 Sep 20. pii: 2026.05.27.728281. [Epub ahead of print]

Conserved Metastatic Cell States and Spatial Immune Microenvironment Remodeling Define Pancreatic Cancer Liver Metastases.

Ayushi Mandloi, Christina R Larson, Tuan M Tran, Sudharonjon Roy, Ateeq M Khaliq, Yu-Hua Dean Fang, Jace Baines, Richard P Laube, Meet Patel, Christopher Risley, Robert S Welner, Satwik Acharyya, Ashiq Masood, Julienne L Carstens.

   Background: Pancreatic ductal adenocarcinoma (PDAC) mortality is driven largely by liver metastatic disease; however, the malignant cell states and tumor microenvironmental features of PDAC liver metastases remain obscure.
Methods: We developed a transplant model system of matched pancreatic and liver tumors to study PDAC metastatic progression. Using this model, we identified murine PDAC cell lines with distinct liver metastatic capacities and performed multiomic profiling of matched primary pancreatic and metastatic liver tumors. Transcriptional programs associated with high and low liver tropism were defined and evaluated across tumor models and independent human PDAC datasets. Spatial and tumor-immune interaction analyses were used to characterize microenvironmental niches, immune composition, and cellular relationships within primary and metastatic tumors.
Results: A high-liver-tropic transcriptional program was enriched in high liver-tropic cell lines and malignant cells within liver metastases, conserved across human PDAC datasets, and associated with inferior patient survival. High- and low-liver-tropic tumor states occupied distinct liver microenvironmental niches and exhibited different tumor-immune communication networks, accompanied by local and systemic changes in immune composition. Liver metastases also displayed features of enhanced immunosuppression, including increased proximity of CD4+ and CD8+ T cells to tumor cells and greater spatial association between regulatory T cells and exhausted CD8+ T cells.
Conclusions: These findings identify conserved PDAC cell states associated with differential liver metastatic capacity and demonstrate that liver metastasis is accompanied by spatial and immunologic remodeling of the tumor microenvironment. Together, the study provides a framework for understanding how tumor-intrinsic metastatic programs interact with site-specific immune ecosystems in PDAC.

Keywords:  Biomarker Gene Signature; Liver Metastasis; Metastatic Tropism; Mouse models; Pancreatic cancer; Spatial infiltration quantification; T cell exhaustion; Targeted Spatial proteomics- COMET; Transcriptomics; Tumor microenvironment

DOI:  https://doi.org/10.64898/2026.05.27.728281
Nat Cancer. 2026 Sep 22.

An iron-regulated methionine redox axis governs adipose browning and cancer cachexia.

Jung Seung Nam, Sung Shin Ahn, Yeonoh Shin, Ariana Vargas-Castillo, Maya S Dixon, Pardis Ahmadi, Kathrin Schilling, Fereshteh Zandkarimi, Alex Chen, Nal Ae Yoon, Harrison Cullen, Yanping Sun, Thomas C Caffrey, Kelsey A Klute, Benjamin J Swanson, Jordan Lu, Samuel Pan, Yuxuan Chen, Shu Ichimiya, Geena Kim, Jeanine M Genkinger, Kazuki Sugahara, Michael D Kluger, Paul Grandgenett, Michael A Hollingsworth, Luke Berchowitz, Anthony W Ferrante, Lori M Zeltser, Sabrina Diano, Iok In Christine Chio.

Adipose browning and atrophy are early events of cachexia, a lethal metabolic disorder affecting nearly half of the population with cancer. Here, using individual-derived specimens and mouse models, we identified an iron-dependent pathway that initiates adipose browning in both physiological and cachectic settings. Upon adrenergic stimulation of adipocytes, an influx of iron induces the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding EXXH motif of two MSRA polypeptides serves to dimerize, stabilize and elevate its reductase activity. Iron-bound MSRA dimers in turn promote adipose browning by maintaining the reduced state of select substrates, including the catalytic subunit of protein kinase A. Remarkably, in mouse models, MsrA deletion impairs adipose browning, mitigates cachexia and prolongs the survival of tumor-bearing animals. Thus, as a key nexus of cancer-associated cachexia, the β3 adrenergic receptor-iron-MSRA axis is a promising target for clinical intervention.

DOI: https://doi.org/10.1038/s43018-026-01234-y
Science. 2026 09 24. 393(6818): eadw8520

Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.

Swagata Goswami, Qiming Zhang, Abdullah Burak Yildiz, Upasana Das Adhikari, Akhouri Kishore Raghawan, Manon Bulliard, Sabhyata Sedhain, Odai Darawshi, Cigdem Elif Celik, Feyza Cansiz, Constantin P Krempe, Jonas Rösler, Gabriele Allies, Sven W Meckelmann, Chiashin Chi, Felix-Levin Hormann, Sven Heiles, Joseph Sedlak, Wesley Grace, George Eng, Ethan Reich, Chiara Alquati, Kevin J Williams, Benjamin J Read, Edrees H Rashan, Zhixin Li, Anup Jnawali, Jose A Ortiz, Chesta Jain, Charles A Whittaker, Osman H Yilmaz, Vikram Deshpande, Oliver J Schmitz, Albert Sickmann, Autumn G York, Douglas S Kwon, Ulf Neumann, Maria Fedorova, Matthew G Vander Heiden, Besim Ogretmen, Nilay S Sethi, Alpaslan Tasdogan, Ömer H Yilmaz.

Mechanisms by which primary tumor cells acquire metastatic capability through metabolic and signaling adaptations are currently poorly understood. We demonstrate that tumor-intrinsic ceramide metabolism, amplified by dietary fat, initiates colorectal cancer metastasis. We observed that dietary fat exposure triggers a sustained increase in de novo ceramide biosynthesis, mediated by the dihydroceramide desaturase Degs1. Ceramide accumulation activates yes-associated protein (YAP) through protein phosphatase 2A (PP2A)-mediated dephosphorylation, promoting a durable shift toward a distinct YAP-driven regenerative (YAP-DR) program, marked by Basp1, that promotes metastasis. Selective elimination of Basp1high cancer cells prevented metastatic seeding. Degs1 loss reduced ceramide levels, YAP activity, YAP-DR signatures, and metastasis without affecting primary tumor growth, whereas blocking ceramide degradation enhanced YAP activity and metastasis. These findings identify ceramide-induced YAP signaling as a key mediator of metastatic initiation, operating independently of primary tumor expansion.

DOI: https://doi.org/10.1126/science.adw8520
Cancer Discov. 2026 Sep 22. OF1-OF6

Targeting RAS for Pancreatic Cancer Interception.

Sandra Misale, Neeha Zaidi, Elizabeth M Jaffee, Alison P Klein, Laura D Wood.

Multiple strategies to target RAS are now available to treat pancreatic cancer. As pancreatic precancers also have KRAS mutations, these tools hold great promise for cancer interception.

DOI: https://doi.org/10.1158/2159-8290.CD-26-1179
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70383

Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles.

Jeremy B Ducharme, Martin M Schonk, Miguel A Gutierrez-Monreal, Leonardo F Ferreira, Karyn A Esser, Andrew R Judge, Sarah M Judge.

   BACKGROUND: Cancer cachexia, a debilitating syndrome characterized by muscle wasting, significantly impacts survival in gastrointestinal cancers like pancreatic cancer. Emerging evidence suggests a link between cancer cachexia and disrupted circadian rhythms in peripheral tissues, including locomotor muscles. However, circadian dysregulation in cardiorespiratory muscles-whose functional decline are suspected to contribute to increased morbidity and mortality in patients experiencing cachexia-remains largely unexplored.
METHODS: Herein, we investigated circadian gene expression patterns in cardiorespiratory muscles during cachexia using the orthotopic KPC pancreatic cancer model. To do this, circadian transcriptomes were generated from diaphragm and heart tissues collected from Sham and KPC mice every 4 h over 24 h, beginning on Day 12 postinoculation, which, based on our prior work, reflects the onset of cachexia in this model. Rhythmically expressed genes (REGs) (Pc < 0.01) were identified using the LR_rhythmicity R package, which evaluates the goodness-of-fit (R2) to a 24-h sinusoidal model of transcript oscillations. Differences in circadian patterns, including changes in amplitude, phase and basal expression, were assessed using the LR_diff R package with p < 0.05.
RESULTS: We found that ~60% of rhythmic genes lost their circadian rhythmicity in both tissues, with distinct shifts in gene networks. Diaphragm disruptions centred on repression in basal expression and/or amplitude of core clock components and rest-phase-dependent disruptions to gene networks governing lipid and oxidative programs of metabolism and proteostasis, which were linked to an upregulation and gain of rhythmicity in inflammatory networks that peaked during the rest phase. Circadian disruptions in the heart involved loss of rhythmicity in gene networks governing cardiac function, including beta-adrenergic and cAMP signalling, cellular responses to insulin and neurogenesis, with a similar, but more limited upregulation of inflammatory networks.
CONCLUSIONS: These findings demonstrate that pancreatic cancer cachexia is associated with widespread circadian dysregulation in cardiorespiratory muscles, potentially contributing to both muscle wasting and functional decline.

Keywords:  cancer cachexia; circadian rhythm; circadian transcriptome; diaphragm; heart; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70383
Science. 2026 Sep 24. 393(6818): eaec5473

Mammals produce cyclo-octasulfur to suppress lipid peroxidation and ferroptosis.

Uladzimir Barayeu, Seiryo Ogata, Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Masanobu Morita, Tomoaki Ida, Mike Lange, Yuka Unno, Saber Boushehri, Paulius Greicius, Akira Nishimura, Lorenzo Catti, Yuexuan Pan, Tianli Zhang, Takayuki Shimizu, Ryo Ushioda, Takakazu Nakabayashi, Seji Asamitsu, Kazuki Fusegawa, Takashi Suzuki, Takanori Ishida, Naoko Tanda, Yasuo Watanabe, Yukihiro Tsuchiya, Ryo Yamaguchi, Shintaro Noguchi, Eikan Mishima, Fumiko Yano, Mieko Arisawa, Dennis J Stuehr, Ning Xia, Huige Li, Bernd Moosmann, Frauke Gräter, Camilo Aponte-Santamaría, James A Olzmann, Marcus Conrad, Albert van der Vliet, Tobias P Dick, Hozumi Motohashi, Michito Yoshizawa, Takaaki Akaike.

Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo-octasulfur (S8). We found that S8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet-associated nitric oxide synthase as a source of S8 biosynthesis and found that S8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.

DOI: https://doi.org/10.1126/science.aec5473
Cell Mol Gastroenterol Hepatol. 2026 Sep 25. pii: S2352-345X(26)00185-2. [Epub ahead of print] 101907

Niche-Specific Stromal Crosstalk in PDAC Liver Metastasis.

Marc Nater, Mara H Sherman.

DOI: https://doi.org/10.1016/j.jcmgh.2026.101907
Nat Rev Cancer. 2026 Oct;26(10): 739-740

From blunt-force treatment to precision: 25 years of transformation in cancer research.

DOI: https://doi.org/10.1038/s41568-026-00980-6
Am J Physiol Cell Physiol. 2026 Sep 19.

Reassessing the Role of Progenitor Cells in Muscle Wasting in Cancer Cachexia.

Spencer G Miller, Abasi-Ama Udeme, Emma Funk, Carlos Alfaro-Quinde, Suganya Subramanian, Stefano Berto, Jian Ouyang, David J Wang, Michael C Ostrowski, Teresa A Zimmers, Denis C Guttridge.

  Skeletal muscles contain myogenic and non-myogenic progenitor cells that proliferate and differentiate after tissue damage to restore myofiber, connective tissue, and blood vessel homeostasis. We previously showed that cancer-induced muscle wasting involves myofiber damage and impaired differentiation of myogenic progenitors, coincident with the aberrant accumulation of mesenchymal progenitor cells expressing both myogenic (Pax7) and non-myogenic (Sca1, Pdgfrα) progenitor markers. Here, we combined lineage tracing and scRNA-seq to more deeply explore muscle resident progenitor cells during cancer cachexia. Colon-26 (C-26) carcinoma cells were injected into adult (≥12-weeks-old) Pax7-CreER; Rosa26-LSL-tdTomato mice, and tamoxifen was administered after tumors were established but prior to cachexia. At cachexia endpoint, scRNA-seq analysis was performed on muscle mononuclear cells. In both control and C-26 muscles, Pax7 and tdTomato transcripts were restricted to myogenic progenitors, whereas Sca1 and Pdgfrα were restricted to non-myogenic progenitors. These results were confirmed by flow cytometry and suggest that mesenchymal progenitor cells do not commit to a myogenic fate during cancer cachexia. However, consistent with earlier findings, our transcriptomic analyses validated that myogenic progenitors from tumor-bearing mice were impaired to differentiate. When we repeated Pax7-lineage tracing and scRNA-seq on young mice (6-week-old) still undergoing developmental muscle growth similar results were obtained, but interestingly, by flow cytometry we detected a small population of Sca1+; tdTomato+ cells, not present in adult muscles. Thus, non-myogenic progenitors might indeed be capable of adopting a myogenic fate during cancer cachexia, but this contributes to only a minor fraction of Pax7+ cells and likely to be age dependent.

Keywords:  Cancer cachexia; atrophy; mesenchymal progenitor cells; muscle stem cells; myogenesis; regeneration; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00144.2026
Nat Aging. 2026 Sep 21.

RamanOmics decodes the spatial vibrational-molecular architecture of senescence in aging and repair.

Ke Zhang, Xingjian Chen, Francesco Monticolo, Salvatore Sorrentino, Haochun Huang, Claire Callahan, Yueqing Qiao, Judy Zhou, Sonia Brodowska, Styliani Sapantzi, Jianhuan Qi, Yinghan Wu, Thai Nam Son Dang, Yanwan Cao, Sumin Kang, Francesca Viggiani, Chia-Kang Ho, Yanxin Xu, Koseki J Kobayashi-Kirschvink, Thang Mung, Hemali Phatnani, Zhixun Dou, Jeon Woong Kang, Peter T C So, Jian Shu.

Aging and tissue repair involve heterogeneous remodeling across transcriptional, biochemical and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how these states co-evolve. Here we present RamanOmics, a multimodal framework integrating label-free hyperspectral Raman imaging with single-nucleus RNA sequencing and spatial transcriptomics to link biochemical states with transcriptional programs at single-cell spatial resolution. Applied to young and old mouse lung and skin, RamanOmics reveals tissue-specific programs: lung senescent cells are enriched for extracellular matrix remodeling and transforming growth factor-β signaling, whereas skin senescence is dominated by epidermal differentiation genes (Krt10, Lor and Sbsn). Across tissues, we identified a conserved lipid-linked Raman signature (1,131-1,135 cm-1) marking p21+ senescent cells and developed a machine learning-derived, multimodal barcode enabling nondestructive senescence identification in situ. In a mouse wound-healing model, RamanOmics reveals reactivation of epidermal differentiation genes (Krt10, Lor and Sbsn) in senescent cells, alongside increased lipid-associated Raman signatures. Together, RamanOmics provides a tissue-agnostic framework for scalable, multimodal profiling of cellular states.

DOI: https://doi.org/10.1038/s43587-026-01219-7
Cancer Res. 2026 Sep 21.

Longitudinal Analysis of Matched Patient Biospecimens Reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Cancer.

Aylin Z Henstridge, Peter A Azorsa, Nandini Arya, Ahmed M Elhossiny, Padma Kadiyala, Molly Goldwasser, Georgina Branch, Vaibhav Sahai, Nicole Peterson, Jorge D Machicado, Richard S Kwon, Allison R Schulman, Erik-Jan Wamsteker, George M Philips, Stacy B Menees, Jonathan Y Xia, Tara L Hogenson, Arvind Rao, Jiaqi Shi, Timothy L Frankel, Filip Bednar, Marina Pasca di Magliano, Costas A Lyssiotis, Mark J Truty, Martin E Fernandez-Zapico, Eileen S Carpenter.

Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). Cytotoxic combination chemotherapy treatments are the mainstay of PDAC therapy, but patients rapidly develop chemoresistance, highlighting the need to elucidate how chemotherapy alters the TME and whether these changes drive chemoresistance. Here, we examined matched pre- and post-treatment tissue specimens using single-cell RNA-sequencing and found near-universal enrichment after treatment of axonal guidance genes in cancer-associated fibroblasts (CAFs). These neural CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrent lesions had the highest prevalence of neural CAFs versus primary tumors and untreated metastases. Neural CAFs showed elevated non-canonical WNT mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Additionally, in vitro studies revealed enrichment of axonal guidance genes in patient-derived CAF lines upon exposure to chemotherapy or tumor cells. Altogether, these findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising therapeutic target for this disease.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0823
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2616901123

Inflammatory memory inactivates AMPK-stimulated DDR1 degradation to enable pancreatic cancer growth.

Fei Yang, Bo Lin, Yongkang Yuan, Zihang Yuan, Xiaohong Pu, Chunlan Wang, Da Zhang, Yang Yang, Kosuke Watari, Rongkui Luo, Jian Zhou, Xinrong Yang, Beicheng Sun, Michael Karin, Hua Su.

  Inflammation and stromal remodeling control pancreatic ductal adenocarcinoma (PDAC), but whether and how these cues are integrated at the molecular level remains unclear. Here, we identify a metabolic checkpoint that controls the stability of the collagen receptor discoidin domain receptor 1 (DDR1), and subsequent tumorigenesis. Defective Col-I remodeling deprives PDAC cells of the high-affinity DDR1 ligand, the ¾Col-I fragment, resulting in reduced cellular adenosine triphosphate (ATP) and activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK phosphorylates DDR1 at T519, promoting its recognition by the E3 ubiquitin ligase adaptor FBXW2 and subsequent proteasomal degradation. Importantly, this degradation pathway can be disabled by inflammatory signals. Exposure to inflammatory cytokines induces methylation-dependent silencing of FBXW2, establishing an inflammatory memory that preserves DDR1 stability, enabling sustained ligand-triggered receptor oligomerization and downstream NF-κB-NRF2 signaling even in PDAC restrictive stromal environments. Together, these findings identify regulated receptor turnover as a mechanism through which stromal architecture, metabolic state, and inflammatory memory are integrated to control PDAC progression.

Keywords:  DNA methylation; collagen cleavage; inflammatory memory; pancreatic cancer; receptor protein stability

DOI:  https://doi.org/10.1073/pnas.2616901123
Cell. 2026 Sep 24. pii: S0092-8674(26)01070-6. [Epub ahead of print]

Resident tissue macrophages transfer selenium transporter protein to protect pancreatic cancer from ferroptosis.

Wei Guo, Ziyi Li, Qihan Chen, Garett Dunsmore, Li Jiang, Zhijie An, Ziwen Fu, Yibo Liu, Yufei Shao, Shulin Zhao, Ting Wang, Huan Tang, Chengjian Zhao, Guangyan Zhangyuan, Jia Liu, Pengyi Liu, Zhaoyuan Liu, Jiawen Qian, Shuangyan Zhang, Minmin Shi, Ding He, Yedan Liu, Camille Blériot, Lai Guan Ng, Fan Bai, Lingxi Jiang, Bing Su, Baiyong Shen, Florent Ginhoux.

  Pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer with a poor prognosis, contains resident tissue macrophages (RTMs) present before tumor onset and monocyte-derived macrophages recruited during tumor development, but their distinct roles in supporting tumor progression remain unclear. Combining single-cell profiling, spatial analysis, lineage tracing, RTM depletion, and selenium tracing, we found that RTMs preferentially localize at the tumor border, where they promote epithelial-mesenchymal transition (EMT), tumor growth, and metastasis. Mechanistically, RTMs transfer the selenium transporter Selenop to EMThi tumor cells through LRP8-dependent uptake, increasing tumor-cell selenium availability, limiting lipid peroxidation, and shielding EMThi tumor cells from ferroptosis. RTM-specific Selenop deletion or tumor-cell Lrp8 disruption reduced EMT and tumor progression, whereas ferroptosis inhibition reversed the effect of RTM depletion. Human PDAC showed border-enriched SEPP1+ RTMs near EMThi tumor cells, suggesting a conserved macrophage-derived selenium niche that supports invasive tumor states and highlighting the potential for targeting RTMs or their secretory factors in PDAC.

Keywords:  EMT; LRP8; PDAC; RTM; Selenop; ferroptosis; macrophages; resident tissue macrophages; selenium

DOI:  https://doi.org/10.1016/j.cell.2026.09.001
Signal Transduct Target Ther. 2026 Sep 22. pii: 398. [Epub ahead of print]11(1):

Cell death: immunogenic potential of cuproptosis in cancer.

Lorenzo Galluzzi, Oliver Kepp, Guido Kroemer.

DOI: https://doi.org/10.1038/s41392-026-02974-0
J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02468-3. [Epub ahead of print] 113596

TRPML1 loss disrupts lysosome-mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy.

Alia K Syeda, Shekoufeh Almasi, Cory J Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Amari Delima-Baril, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Unnikrishnan B Sheela, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.

Signaling mechanisms at the lysosome-mitochondria interface form a critical network that enables cancer cells to maintain mitochondrial quality control, adapt to metabolic stress, and survive therapy. However, the incomplete understanding of the mechanisms coordinating this network has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we identify TRPML1 as an important regulator of lysosome-mitochondrial communication in MDA-MB-231 TNBC cells. We find that TRPML1 knockdown (ML1-KD) impaired mitochondrial respiration, oxidative substrate utilization, ATP production and redox balance in MDA-MB-231 cells, whereas comparable changes were not observed in non-cancerous MCF10A cells. ML1-KD reduced lysosomal acidification and impaired autophagic flux and was accompanied by reduced TFEB nuclear localization, impaired mitophagy, and alterations in mitochondrial maintenance proteins. These changes were accompanied by organellar proximity remodelling, with increased mitochondria-ER proximity and reduced mitochondria-lysosome proximity, together with altered cytosolic/mitochondrial Ca2+ responses, broad metabolic remodelling, G0/G1 arrest, and caspase-3/7-independent cell death. Importantly, ML1-KD cells showed enhanced responses to otherwise subeffective concentrations of doxorubicin and paclitaxel. Together, our findings support TRPML1-dependent lysosomal signaling as an important contributor to mitochondrial-metabolic resilience and chemotherapy responsiveness in MDA-MB-231 TNBC cells.

DOI: https://doi.org/10.1016/j.jbc.2026.113596
EMBO Rep. 2026 Sep 25.

LC3 forms functional nanoclusters on autophagosomes.

Saman Fatihi, Deepak M Khushalani, Joydipta Kar, Sourav Ghosh, Aayushi Singh, Suvapriya Roy, Anirban Banerjee, Nitin Mohan, Lipi Thukral.

Autophagosome biogenesis depends on the coordinated action of proteins and lipids. However, how LC3B organizes at high density and contributes to autophagy-associated functions remains unclear. Using molecular dynamics simulations and super-resolution microscopy, we show that LC3B self-assembles into higher-order nanoclusters approximately 150 nm in size. These clusters form spatially distinct LC3B "islands" on the autophagosome membrane and show a preferential association with phosphatidylinositol-3-phosphate (PI3P) lipids. Molecular analysis of 296 structural clusters reveals a putative LC3B homo-clustering interface characterized by a distinct alternating hydrophobic-polar motif. To experimentally validate this interface, we generated four LC3B mutants targeting the clustering motif. STORM imaging of the LC3 mutants demonstrates a complete alteration in clustering dynamics, with diffuse, smaller LC3 clusters on the autophagosome. Further, motility analysis and interaction with the autophagic adaptor protein FYCO1 show abrogated autophagosome motility. Finally, loss of LC3B nanoclustering also significantly compromises autophagic entrapment of Streptococcus pneumoniae and results in elevated intracellular bacterial survival. Taken together, our results reveal LC3 clustering as a potential organizing principle that coordinates the spatial and temporal dynamics of autophagy.

DOI: https://doi.org/10.1038/s44319-026-00931-0
Neuro Oncol. 2026 Sep 25. pii: noag129. [Epub ahead of print]

Cancer Neuroscience: Establishing a home in Neuro-Oncology.

Shawn L Hervey-Jumper, Michelle Monje, Frank Winkler, David H Gutmann.

  Although neurons innervate all organs in which solid tumors grow, the role of neurons in cancer biology has long been neglected. Over the past decade, numerous studies have elucidated the critical role of the nervous system in cancer pathophysiology, culminating in the birth of Cancer Neuroscience. The recognition that neurons dictate many aspects of tumor biology not only provides new opportunities for therapeutic targeting of these stromal dependencies but also underscores the strong bi-directional relationships between tumors and the nervous system that result in cancer-associated symptomatology. By recognizing the key place of neurons in tumor biology, Cancer Neuroscience has ushered in a new era in which brain cancers should be conceptualized as diseases of dysregulated neurodevelopment, neuroplasticity, and neurophysiological function, usurped to drive brain cancer growth, progression, and therapeutic resistance. Likewise, the nervous system governs the initiation, growth, spread, and survival of most (if not all) extracranial cancers, while also mediating communication from cancers to the brain. Herein, we outline the current state of Cancer Neuroscience and the roles for neuro-oncologists in this new aspect of cancer care as an introduction to an upcoming series of articles in Neuro-Oncology on cellular interactions in the healthy nervous system and in the setting of cancer.

Keywords:  Cancer Neuroscience; astrocytoma; cancer; glia cells; glioma; neuron; synapse

DOI:  https://doi.org/10.1093/neuonc/noag129
J Cell Sci. 2026 Sep 24. pii: jcs.265302. [Epub ahead of print]

In situ visualization of autophagy reveals the presence of vesicles at the expanding phagophore rim.

Claire Ortmann de Percin Northumberland, Mariya Licheva, Rahel Dabrowski, Rubén Gómez-Sánchez, Sabrina Berkamp, Philipp Schönnenbeck, Martin Graef, Claudine Kraft, Carsten Sachse.

  The autophagy core machinery mediates the enclosure of cytosolic cargo destined for degradation in the lysosome. The Atg9-Atg2-Atg18 complex coordinates phagophore expansion via directed lipid transfer until closure of the phagophore rim. Using an Atg2 variant (Atg2-PM4) as a model of decelerated autophagosome biogenesis, we visualized the morphological states prior to autophagosome closure by cryogenic correlative light and electron microscopy in S. cerevisiae. Using in situ cryo-electron tomography, we find an enlarged rim morphology of an expanding phagophore in Atg2-PM4 cells in comparison with Atg2 wildtype condition. Analysis of segmented rim membrane features reveal surrounding and membrane-attached vesicles. The dimensions of the enlarged rims are consistent with fusion of cytosolic vesicles with the growing phagophore. High-resolution imaging in this study suggests that, apart from the initial nucleation phase, vesicle fusion can also contribute to phagophore expansion during later stages of autophagosome biogenesis.

Keywords:  Atg2; Autophagosome biogenesis; Autophagy; Correlative light and electron microscopy; Cryo-electron microscopy; Lipid transfer; Membrane analysis; Phagophore expansion

DOI:  https://doi.org/10.1242/jcs.265302
Nat Commun. 2026 Aug 24. pii: 10137. [Epub ahead of print]17(1):

Load-dependent RGD-context sensing via αV-class integrins reprograms cell adhesion and mechanics.

Upnishad Sharma, Jakob M Reber, Jonne Helenius, Cara Buchholz, Reinhard Fässler, Nico Strohmeyer, Daniel J Müller.

The biochemical and mechanical properties of extracellular matrix proteins govern cell adhesion, mechanics, and migration. How cells use integrins to discriminate between the arginine-glycine-aspartic acid motifs presented by different extracellular matrix proteins, a process central to tissue homeostasis and disease, has remained unclear. Here we show that mammalian cells mount a distinct "biphasic" mechanical response through αV-class integrins to the arginine-glycine-aspartic acid motif of vitronectin compared with fibronectin, osteopontin, and cyclic arginine-glycine-aspartic acid. Within seconds of contact with vitronectin, we find that αV-class integrins strengthen cell adhesion through two load-dependent mechanotransduction pathways in which αVβ3 and αVβ5 integrins take complementary roles. Under low load, we demonstrate that the first phase requires both integrins together with an intact, pre-tensed actomyosin cortex, talin, paxillin, and focal adhesion kinase activity, with αVβ5 integrin additionally engaging clathrin-mediated endocytosis. Under higher load, we show that the second phase is dominated by αVβ3 integrin-directed actin-related protein 2/3, cellular Src kinase, and phosphatidyl inositol-3-kinase signaling, which organizes the consensus adhesome, while αVβ5 integrin concurrently drives cellular stiffening. Taken together, we find that αV-class integrins rapidly deploy arginine-glycine-aspartic acid -motif- and β-subunit-specific programs that cooperatively tune cell adhesion and mechanics according to the extracellular matrix composition.

DOI: https://doi.org/10.1038/s41467-026-77028-8
bioRxiv. 2026 Sep 17. pii: 2026.09.15.751463. [Epub ahead of print]

A quantitative redox proteome of the human muscle response to exercise.

Yu Lei, Jonathan J Petrocelli, Anita Reddy, Carlos Henríquez-Olguin, Nils Burger, Sanghee Shin, Bingsen Zhang, Taylor Covington, Markus Waldeck-Weiermair, Jiuchun Zhang, Shelley M Wei, Thomas E Jensen, Christian T Voldstedlund, Christian S Carl, Bente Kiens, Erik A Richter, Edward T Chouchani.

Reactive oxygen species (ROS) regulate protein function through reversible cysteine oxidation. In human skeletal muscle, exercise-induced ROS initiates adaptations such as mitochondrial biogenesis, increased insulin sensitivity, and hypertrophy. However, specific protein targets of ROS regulation during exercise remain unclear owing to longstanding challenges in analyzing redox proteomes in vivo . We applied cysteine derivatization and multiplexed proteomics to map muscle protein cysteine oxidation in humans during exercise. The OxiMuscle dataset quantifies reversible modifications across 9,177 unique cysteine sites on 2,782 proteins, comprising 17,492 individual cysteine site measurements in young men undergoing three types of exercise, providing the first comprehensive, site-resolved and quantitative analysis of the exercise-regulated redox cysteine proteome in humans. We systematically define cysteine oxidation targets regulated by at least one form of exercise, many of which reside in proteins with established roles in muscle physiology. Among these sites is a redox-regulated cysteine on the autophagy receptor protein p62. We demonstrate that reversible oxidation of this cysteine regulates p62-mediated autophagy upon myotube contraction and mouse muscle adaptation to exercise in vivo . Together, these results define a redox-driven mechanism linking exercise-induced autophagy to muscle adaptation. More broadly, our findings offer a comprehensive resource on redox-signaling networks in human muscle, accessible at http://oximuscle-alb-1899330623.us-east-1.elb.amazonaws.com/ .

DOI: https://doi.org/10.64898/2026.09.15.751463
Sci Adv. 2026 Sep 25. 12(39): eaec7037

Cell-intrinsic functions of PD-L1 activate autophagy and prevent cytokine-induced apoptosis.

Mihaela Stefan-Lifshitz, Nicola Viola, Olga Meshcheryakova, Crystal Nieves Garcia, Pamela Mattar, Zhengzi Yi, Marie Louise Aoun, John C McAuliffe, Jonathan Smith, Vikas Mehta, Richard V Smith, Adam J Gersten, Weijia Zhang, Rajat Singh, Yaron Tomer.

Immune checkpoint inhibitor (ICI) therapy triggers complications that are currently attributed solely to immune activation. We hypothesized that target tissue-specific mechanisms also play a role and studied these mechanisms in thyrocytes. We found that thyroidal PD-L1 acts as a cytoprotective regulator, promoting cell survival during cytokine-induced stress. PD-L1 suppression in thyrocytes amplified interferon-γ-driven stress by aberrantly activating AKT-ERK-mTORC1, inhibiting autophagy, augmenting cellular stress, and triggering apoptosis. In a mouse model of ICI-thyroiditis, anti-PD-L1 treatment triggered immune activation while promoting thyrocyte apoptosis. Mechanistically, in mice, both pharmacologic and genetic down-regulation of thyroidal PD-L1 caused autophagic defects. Our findings reveal a role for PD-L1 in protecting thyroid tissue from cytokine-mediated stress and suggest that anti-PD-L1 tissue toxicity may reflect both an immune-mediated attack and intrinsic cellular vulnerability. Our data provide a broader framework for understanding ICI adverse events and for guiding the development of treatment strategies.

DOI: https://doi.org/10.1126/sciadv.aec7037
Clin Colorectal Cancer. 2026 Sep 02. pii: S1533-0028(26)00066-6. [Epub ahead of print]

A Phase I Study of Nab-Paclitaxel, Gemcitabine and AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas: ECOG-ACRIN EA2131.

Jennifer R Eads, Ju-Whei Lee, Cheng E Chee, Neal J Meropol, Al B Benson, Paul Catalano, Efrat Dotan, Dana B Cardin, Peter J O'Dwyer.

   PURPOSE: Pancreatic adenocarcinoma is a devastating disease for which there are limited treatment options. Identification of novel agents to enhance the activity of existing regimens is much needed. We hypothesized that the disruption of the DNA damage response by AZD1775, an oral Wee1 inhibitor, added to the nab-paclitaxel and gemcitabine chemotherapy backbone would be safe and effective.
METHODS: A phase I trial to evaluate the dose-limiting toxicities and maximum tolerated dose of AZD1775 in combination with nab-paclitaxel and gemcitabine was conducted in patients with metastatic or locally advanced, unresectable pancreatic adenocarcinoma (NCT02194829). A total of 7 patients received nab-paclitaxel and gemcitabine intravenously on days 1, 8, and 15 of a 28-day treatment cycle, along with AZD1775 by mouth on days 1, 2, 8, 9, 15, and 16. Toxicities were assessed using CTCAE version 4 criteria.
RESULTS: Two patients were treated at the initial dose level of nab-paclitaxel, gemcitabine, and AZD1775, and both experienced dose-limiting toxicities (dehydration, elevated bilirubin, oral mucositis, increased AST, and Candida intertrigo). Under a revised study design, 5 patients were treated, and 2 of them also developed dose-limiting toxicities (anemia, thrombocytopenia, neutropenia, hyponatremia, and febrile neutropenia). Progression-free survival (PFS) and overall survival (OS) among these 7 patients were 5.26 months (95% confidence interval [CI] [2.73, 12.16]) and 5.29 months (95% CI [2.73, 20.17]), respectively.
CONCLUSION: The combination of nab-paclitaxel, gemcitabine, and AZD1775 was determined to be too toxic when administered in patients with metastatic or locally advanced, unresectable pancreatic adenocarcinoma.

Keywords:  Cell cycle checkpoint inhibition; Clinical trial; Pancreatic cancer; Toxicity; Wee1

DOI:  https://doi.org/10.1016/j.clcc.2026.08.004
Nat Commun. 2026 Aug 22. pii: 10054. [Epub ahead of print]17(1):

Differential lipid selectivity of StARD phospholipid transporters revealed by native MS.

Carla Kirschbaum, Sophie A S Lawrence, Jack L Bennett, Olivia B Ramsay, Yara Ahmed, Tarick J El-Baba, Stefano Vanni, Carol V Robinson.

Intracellular lipid transport in eukaryotes is largely mediated by lipid transfer proteins (LTPs). Transport kinetics differ markedly among lipid species, implying selective lipid recognition by the involved proteins. Here, we characterize endogenous ligands of the human phospholipid transporters STARD2, STARD7, and STARD10 by multistage native mass spectrometry (MS). Our results demonstrate that they exhibit distinct lipid selectivities, with STARD7 binding a broad range of phospholipids, whereas STARD2 and STARD10 preferentially copurify with poly- and di-unsaturated phospholipids, respectively. We link this acyl chain selectivity to tissue-specific LTP expression patterns and show that LTP expression levels modulate lipid metabolism. Through site-directed mutagenesis and molecular dynamics simulations, we further identify a conserved arginine that is essential for phospholipid binding in STARD7 but dispensable in STARD2 and STARD10. To investigate regulation of LTP activity, we mapped phosphorylation sites by native top-down MS and found that STARD2 and STARD10 are phosphorylated in membrane-binding regions. Liposome-based assays revealed that phosphorylation abolishes lipid transfer activity of STARD10 and that lipid selectivity influences the transfer rates of different lipid probes. Together, our results demonstrate that LTPs exhibit distinct lipid binding preferences and suggest that cells finely tune lipid homeostasis by regulating LTP expression levels and activity.

DOI: https://doi.org/10.1038/s41467-026-76988-1
ACS Sens. 2026 Sep 21.

Enhanced Ratiometric Indicators for (Sub)cellular Detection of Magnesium(II) Ions by Flow Cytometry.

Michael Brady, Mu-Chun Liu, Veronika Shchepetkina, Daniela Buccella.

  Magnesium(II) plays essential roles in cellular physiology, yet the inner workings of its cellular distribution and transport remain challenging to study due to the scarcity of tools for Mg2+-selective detection with high spatiotemporal resolution and compatible with high-throughput analysis. We report herein MagZet2, a next-generation ratiometric fluorescent sensor featuring a quinoline dicarboxylate motif with an expanded dynamic range for Mg2+ detection by fluorescence microscopy and flow cytometry. MagZet2 displays excellent Mg2+/Ca2+ selectivity and an apparent dissociation constant, K'd = 0.4 mM, well matched to physiological free Mg2+ concentrations in mammalian cells. By conjugation to HaloTag, we further engineer MagZet2 into chemigenetic indicators that retain desirable photophysical properties of the small molecule counterpart while enabling genetically encoded control of subcellular localization. Using a hybrid sensor, MagZet2(L2)Halo, we demonstrate the first organelle-resolved Mg2+ detection by flow cytometry, a technique that does not inherently offer spatial resolution. Finally, we apply MagZet2(L2)Halo to monitor Mg2+ uptake kinetics in live Caco-2 cells, revealing transport dynamics that parallel those measured using destructive 25Mg transport assays while offering improved temporal resolution and compatibility with live-cell analysis. Together, these results establish MagZet2 and its chemigenetic derivatives as powerful tools for organelle-resolved, high-throughput interrogation of free Mg2+ in living cells.

Keywords:  flow cytometry; fluorescence microscopy; fluorescent indicator; live cell imaging; metal ions; metal transport

DOI:  https://doi.org/10.1021/acssensors.6c01904
PLoS Pathog. 2026 Sep 22. 22(9): e1014614

Role of PRMT5 in regulating ferritinophagy during Mycobacterium tuberculosis infection.

Smriti Sundar, Raju S Rajmani, Kithiganahalli Narayanaswamy Balaji.

Mycobacterium tuberculosis (Mtb) increases the availability of free iron, resulting in ferroptosis of macrophages to facilitate its survival and dissemination. A critical factor for elevated levels of labile iron is the overt accumulation of nuclear receptor coactivator 4 (NCOA4), which promotes autophagic degradation of ferritin in a process termed ferritinophagy. Here, we identify a novel post-translational modification on NCOA4 that is essential for its interaction with ferritin in the iron-replete condition of Mtb-infected cells. Specifically, protein arginine methyltransferase 5 (PRMT5) confers symmetric dimethylation on NCOA4, which promotes ferritinophagy-mediated ferroptosis. Using loss-of-function studies, we show that PRMT5 is required for lipid peroxidation, bacterial survival, and dissemination in Mtb-infected mice. Additionally, the overexpression of a methylation-deficient mutant of NCOA4 phenocopies the depletion of PRMT5 and reduces ferritinophagy in Mtb-infected cells. Mechanistically, we identify that PRMT5-mediated methylation enhances the cytoplasmic retention of NCOA4 and reduces its nuclear availability. Thus, our findings uncover the key interaction between NCOA4 and ferritin that regulates ferroptosis and mycobacterial survival during infection. Perturbation of this interaction results in reduced Mtb loads and alleviated disease pathology.

DOI: https://doi.org/10.1371/journal.ppat.1014614
bioRxiv. 2026 Sep 14. pii: 2026.09.13.750663. [Epub ahead of print]

Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage.

Ryan Elbashir, Keene L Abbott, Diya L Ramesh, Ahmed Ali, Anna Shevzov-Zebrun, Anna M Barbeau, Michelle Wu, Abigail P Ward, Yetiş Gültekin, Brian T Do, Sharanya Sivanand, Azucena Ramos, Tenzin Kunchok, Millenia Waite, Edrees H Rashan, Muhammad Bin Munim, Michael T Hemann, Matthew G Vander Heiden.

Proliferating cells must acquire nucleotides to support DNA replication, yet how cells meet these nucleotide demands for proliferation under physiological conditions remains understudied. Here, we investigated how physiological nutrient availability shapes nucleotide acquisition strategies in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). To assess how environmental nutrients impact nucleotide metabolism, we formulated a mouse plasma-like medium (MPM) that reproduces the circulating metabolite composition of plasma from mice with B-ALL and assessed how this influenced nucleotide metabolism relative to standard culture conditions, where nucleotide acquisition has historically been studied. We find that leukemia cells cultured in MPM acquire nucleotides through salvage pathways, and that select nucleotide salvage pathways are required for proliferation under physiological conditions. Of note, this dependency on nucleotide salvage in plasma-like conditions was not caused by precursor metabolite limitation for de novo synthesis. Instead, we found that physiological folate levels are insufficient to support deoxynucleotide triphosphate (dNTP) synthesis for genome replication, leading to DNA replication stress and impaired proliferation when nucleotide salvage is disrupted. Consistently, dietary folate restriction exacerbates the impaired leukemia progression phenotype of nucleotide salvage-deficient B-ALL cells. Together, these findings demonstrate that access to folates is an endogenous limitation for nucleotide synthesis in plasma-like nutrient conditions, increasing the relevance of nucleotide salvage pathways for leukemia progression. More broadly, this work highlights how micronutrient abundance can influence metabolic dependencies and reveals that folate levels shape nucleotide metabolism under physiological conditions.

DOI: https://doi.org/10.64898/2026.09.13.750663
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2625189123

Positive selection screen identifies natural product β-catenin inactivators.

Matthew W Boudreau, Vitor F Freire, Sophie C Corbett, Lucero Martínez-Fructuoso, Shilpa R Shenoy, Wenyu Yu, Rohitesh Kumar, Christopher C Thornburg, Rhone K Akee, Brian D Peyser, Qinqin Jiang, Jennifer Splaine, Jamie L Pfaff, Dongli Yu, Benjamin C Chandler, Dinah M Abeja, Katherine A Donovan, Jianwei Che, Benjamin L Lampson, Mariana Cooke, Marcelo G Kazanietz, Patricia Szajner, Jennifer A Smith, Vidyasagar Koduri, Tanja Grkovic, Barry R O'Keefe, William G Kaelin.

  Many genetically validated targets in cancer, including the transcription factor β-catenin (β-cat), have historically been viewed as undruggable. Cell-based phenotypic screening of chemical compounds can reveal unanticipated biological and pharmacological principles. Natural products are powerful probes because of their superior structural diversity, drug-like properties, and biological activities as compared to unoptimized synthetic compounds. We screened 326,304 natural product mixtures (40,744 extracts and 285,560 fractions derived from them) using mammalian cells expressing an oncogenic version of β-cat fused to a suicide protein. Multiple fractions degraded the β-cat fusion protein or drove it into a compartment where both fusion partners were apparently inactive. The active natural product from one of the latter specifically activates novel, but not classical, protein kinase Cs and thereby relocates β-cat to juxtamembrane vacuolar structures. These findings suggest a path for inactivating oncogenic β-cat and underscore the power of screening natural product collections with robust phenotypic assays.

Keywords:  chemical biology; natural products; phenotypic screening; β-catenin

DOI:  https://doi.org/10.1073/pnas.2625189123
bioRxiv. 2026 Sep 17. pii: 2026.09.15.751777. [Epub ahead of print]

Melanoma evolution in the lymph node shapes systemic outcomes.

Katherine S Ventre, Tara Muijlwijk, Robert Stagnitta, Shi Qiu, Ze Chen, Irineu Illa Bochaca, Ata S Moshiri, Teresa Davoli, Iman Osman, Itai Yanai, Markus Schober, Amanda W Lund.

Lymph node (LN) metastasis predicts poor patient outcomes, but the mechanistic drivers that shape metastatic fitness, immune evasion, and clinical impact remain elusive. While preclinical models indicate that active tumor adaptation is necessary for LN metastasis, observations of clonal heterogeneity in human tumors has supported a stochastic model of passive and continuous seeding. Reconciling LN metastasis as a passive or active process is essential to understanding if LN metastasis is simply a marker of disease progression or a clinically informative therapeutic target. Here, we report evidence that LNs are active niches that facilitate ongoing melanoma evolution to progressively subvert immune surveillance and enable progression. To construct a spatial trajectory of LN metastasis, we examined paired primary melanomas and metastatic sentinel LNs through integrated genomic, phenotypic, and immunologic analyses. In contrast to a model of continuous seeding, we observe that early dissemination from the primary tumor is followed by extensive intra-nodal diversification, indicating that metastatic outgrowth requires ongoing adaptation within the LN. As clones evolve in the LN, they re-differentiate towards a melanocytic state and reprogram the microenvironment for immune exclusion. In further evolved clones, loss of inflammatory interferon signaling and induction of p53 and mitochondrial stress are associated with decreased overall survival. Collectively, these results implicate the LN as a critical battleground for melanoma progression, where tumor evolution drives adaptation and immune escape to biologically link regional metastasis to patient survival.

DOI: https://doi.org/10.64898/2026.09.15.751777
EMBO Rep. 2026 Sep 25.

ATG8 protein clustering: a HOTS topic in autophagy.

Yongjia Duan, James H Hurley.

DOI: https://doi.org/10.1038/s44319-026-00930-1
J Cell Sci. 2026 Sep 15. pii: jcs264835. [Epub ahead of print]139(18):

The mechanisms and mechanics of aging.

Anastasia Zhurikhina, Maia Kirkegaard, Alberto Guarnieri, Hanna L Martens.

  Aging tissues paradoxically stiffen while losing mechanical resilience, becoming fragile, poorly regenerative and chronically inflamed. We review evidence that these phenotypes emerge from progressive failure of mechanotransduction across a mechanically integrated axis linking extracellular matrix (ECM) architecture, integrin adhesions, cytoskeletal force transmission and nuclear mechanics. We discuss how matrisome remodeling, glycation-driven crosslinking and reduced ECM turnover alter not only bulk stiffness but also fiber deformability, ligand presentation and matrix remodelability, thereby lowering the fidelity of mechanosensing. We then synthesize how distorted mechanical inputs and age-intrinsic changes in mechanotransduction machinery propagate through focal adhesion signaling, actin-microtubule dynamics, mechanosensitive ion channels and nucleo-cytoskeletal coupling to dysregulate mechanosensitive transcription factors (including YAP/TAZ and MRTF), promote senescence and amplify the senescence-associated secretory phenotype (SASP), which further degrades the ECM. Finally, we highlight premature aging syndromes as causal evidence showing that disruption of either ECM structure or nuclear integrity can collapse mechanotransductive homeostasis and trigger tissue degeneration. Together, these studies support a mechanical drift framework and motivate rejuvenation strategies aimed at resetting the aged mechanochemical niche.

Keywords:  Aging; ECM; Mechanosensing; Mechanotransduction; Nucleus; Senescence

DOI:  https://doi.org/10.1242/jcs.264835
bioRxiv. 2026 Sep 18. pii: 2026.09.11.751090. [Epub ahead of print]

Multi-Modal Kinome Profiling Discovers Mesenchymal-Like Polarity Networks that Underly Directed Hepatocellular Carcinoma Cell Migration.

Thankhoe A Rantso, Kathryn Woods, Paige Jensen, Katie A Walker, Alexandria M Chan, Kathleen M Maguire, Rebecca G Zitnay, Lotfa H Lovely, Jingshu Yang, Augustine Takyi, Paul Stewart, Kimberley Evason, Robert L Judson-Torres, Martin Golkowski.

Metastasis and associated therapy resistance remain the principal drivers of cancer related death, and there is a pressing need for a deeper mechanistic understanding and anti-metastatic therapies. For patients that suffer from hepatocellular carcinomas (HCCs), which are the most common primary liver cancers, frequent systemic metastasis results in bleak 5-year survival prognoses of only 4%. To metastasize, carcinoma cells must acquire an invasive phenotype, which typically requires switching from an epithelial-like apical-basal polarity to the front-rear polarity of mesenchymal-like cells. Signaling cues that originate in the tumor microenvironment can activate cellular morphogenic programs that drive polarity switching, like the epithelial-mesenchymal transition (EMT). Protein kinases control most cell signaling pathways and are highly actionable drug targets; however, systematic studies determining the kinases that underly the epithelial-mesenchymal polarity switch (EMPS) are lacking. We developed an assay platform that integrates mass spectrometry (MS)-based kinome profiling, broadly capturing kinase network activity, with chemical genetic screening using selective kinase inhibitors and quantitative phase imaging (QPI), serving as the phenotypic readout. Applying this approach that we dubbed morphokin-MS, to epithelial-like HCC cell lines that we induced to undergo EMPS identified a conserved network of 12 kinases that contributed to HCC cell polarity switching and directed cell migration; MS-based kinome profiling of 17 HCC patient tumors showed that these kinase are frequently upregulated in human tumors. morphokin-MS also revealed that death-associated protein kinase 3 (DAPK3) is one of the principal drivers of the EMPS and directed HCC cell migration. Thus, our mechanistic studies revealed that DAPK3 forms a complex with DAPK1 and filamin-A inter-acting protein 1-like (FILIP1L), which act as scaffold proteins that recruit DAPK3 to the centrosome. Pharmaco-logical and genetic inhibition of the DAPK1-DAPK3-FILIP1L complex blocked centrosome repositioning and microtubule polarization toward the leading edge of mesenchymal-like HCC cells, directed cell migration, and invasion. Our morphokin-MS method and comprehensive kinome profiling data will serve as a valuable resource for the cancer research community; our discovery of an inducible mesenchymal-like DAPK1-DAPK3-FILIP1L polarity complex that controls centrosome positioning in motile HCC cells may lead to the development of novel therapeutics for combatting cancer metastasis.

DOI: https://doi.org/10.64898/2026.09.11.751090