bims-cagime 2026-08-02 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–08–02
28 papers selected by
Kıvanç Görgülü, Technical University of Munich

The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.
Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells.
Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.
Prostaglandin E2 drives cancer-associated cachexia.
Mechanical forces stimulate Golgi export.
Cellular lipid imaging at the ultrastructural level.
Murine pancreatic tumors induce pathological remodeling of muscles critical to chewing and swallowing.
Coupling between sterol and sphingolipid structure in ordered membrane domains.
Ferroptotic propagation: from single-cell execution to tissue-scale death programs.
Multiple distinct metastatic cell states are induced by epithelial-mesenchymal plasticity.
Organelle proteomics of human, neonatal pig, healthy and diabetic mouse islets.
A New Anatomy of Autophagic Clearance: On the Roles of Intrinsic Disorder in the Membrane-Less on Membrane-Encapsulated Mechanism.
CellTune: an integrative software for accurate cell classification in spatial proteomics.
The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples.
Quantitative profiling of basal and stress-induced ribosome collisions.
Oxidized protein states define metastatic fitness in lung cancer.
Microscale matrix defects suppress tension-dependent protrusions and stall collective cell migration.
Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma.
Cumulative microscopy reveals cellular states in fibroblasts from patients with genetic disorders.
Timing the strain: skeletal muscle clock as regulator of physical activity.
CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.
Actin Quantification Using the Filamentous Actin Segmentation Tool (FAST).
The evolution of steady-state laurdan fluorescence: From model membranes to cellular applications.
Routes of Cancer Dissemination: Distinguishing Lymphatic and Hematogenous Spread from Venous Entry to Systemic Arterial Distribution.
Sterol Flux Rewiring: Cholesterol Biosynthesis as a Dynamic Signaling Network.
Nanoscale-Sensitive VSFG Microscopy for Identifying Breast Tumor in FFPE Samples.

bioRxiv. 2026 Jul 14. pii: 2026.07.13.738221. [Epub ahead of print]

The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.

Anupriya Singhal, Kate Ryan, Samuel A Rose, Hannah C Styers, Jung Yun Kim, Nikhita Pasnuri, Ashlyn Moore, Jose Meza-Llamosas, Emma Chen, Josephine Adams, Ananya Nandula, Roshan Sharma, Zhuxuan Li, Tal Nawy, Yan Yan, Nuray Tezcan, Olca Basturk, Mara H Sherman, Dana Pe'er, Tuomas Tammela.

Intra-tumoral heterogeneity is a cardinal feature of solid tumors, yet how distinct cancer cell states functionally contribute to malignant and stromal diversity in situ remains poorly understood. Using mouse models to lineage-trace or genetically ablate the two predominant cancer cell states in autochthonous pancreatic ductal adenocarcinoma (PDAC), we discover that basal cancer cells are highly plastic, whereas classical cancer cells exhibit limited plasticity. Strikingly, ablation of the basal, but not the classical, state induced rapid and durable tumor collapse, driven by loss of immunosuppressive cancer-associated fibroblasts, macrophage repolarization, and reprogramming of the tumor cytokine milieu, culminating in tumor destruction by cytotoxic lymphocytes. Knockout of a single cytokine, GM-CSF, specifically in basal cells recapitulated macrophage repolarization and lymphocyte recruitment observed upon basal state ablation and shrank tumors. These results reveal the basal cell state controls an immunosuppressive cell circuit critical for PDAC maintenance, motivating therapeutic targeting of the basal cells.

DOI: https://doi.org/10.64898/2026.07.13.738221
Science. 2026 Jul 30. 393(6810): eady0832

Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.

Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

DOI: https://doi.org/10.1126/science.ady0832
Immunity. 2026 Jul 28. pii: S1074-7613(26)00276-1. [Epub ahead of print]

Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells.

Yassmin A Elbanna, Maria Tello-Lafoz, Aliya Holland, Ye Zhang, Chengyuan Li, Seema Amin, Zhenghan Wang, Jun-Goo Kwak, Alexandrina Yakimov, Anastasiia Vaska, Esther Lee, Myra Dada, Samuel Vayner, Sarah M Duquette, Young Hun Kim, Jahkwaun Budhai, Ning Fan, Erik Ladewig, Tejus A Bale, Benjamin Y Winer, Kenny K H Yu, Joan Massagué, Christina Leslie, Jungwoo Lee, Ori Barzilai, Scott R Manalis, Morgan Huse.

  Metastatic microenvironments vary widely not only in their biochemical composition but also in their mechanical properties. Here, we examined how the mechanical rigidity of the metastatic niche affects metastases seeding and the local efficacy of antitumor immunosurveillance. Cancer cells stiffened in response to increasing environmental rigidity, a biophysical change that mechanically sensitized them to killing by cytotoxic lymphocytes. In immunodeficient mice, rigidity sensing by cancer cells yielded robust bone colonization, accompanied by marked stiffening of the cancer cells themselves. Conversely, in immunocompetent hosts, stiffer cancer cells were selectively eliminated, and bone metastasis was suppressed. In patients, metastatic cell stiffness was associated directly with environmental rigidity and inversely with immune infiltration. Expression of Spp1, encoding the secreted glycoprotein osteopontin, defined a subset of cancer cells that expanded in the bone, and deletion of Spp1 limited environmentally induced cancer cell stiffening, bone colonization, and immune vulnerability. Thus, environmental mechanosensing regulates both metastases seeding and antitumor immunity, providing an immunological basis for metastatic site selection.

Keywords:  NK cell; bone; cytotoxic T cell; immunosurveillance; lung; mechanobiology; metastasis; metastatic site selection; osteopontin; stiffness

DOI:  https://doi.org/10.1016/j.immuni.2026.06.025
bioRxiv. 2026 Jul 20. pii: 2026.07.17.739092. [Epub ahead of print]

Double-bond geometry determines fatty acid metabolic fate and ferroptosis sensitivity.

Cynthia A Harris, Shunji Kato, Yurika Otoki, Elisa Martin Perez, Dylan Boone, Juan Lorenzo B Pablo, Anna Greka, James A Olzmann.

Ferroptosis is driven by the accumulation of oxidatively damaged membrane phospholipids, making membrane lipid composition a central determinant of cell death sensitivity. While fatty acid chain length and degree of unsaturation are well-established regulators of ferroptosis, whether fatty acid stereochemistry contributes to ferroptosis susceptibility is mostly unexplored. Here, we systematically screened structurally diverse fatty acids for their ability to modulate ferroptosis and unexpectedly identified trans-unsaturated fatty acids as potent sensitizers. Compared with its cis counterpart linoleic acid, the trans polyunsaturated fatty acid (PUFA) linoelaidic acid more strongly enhanced lipid peroxidation and promoted the accumulation of ferroptosis-susceptible phospholipid species. Unexpectedly, the trans monounsaturated fatty acid petroselaidic acid also sensitized cells to ferroptosis, whereas its cis stereoisomer petroselinic acid suppressed ferroptosis. Mechanistically, petroselaidic acid required stearoyl-CoA desaturase-dependent conversion to a PUFA, directly demonstrating that double-bond geometry can redirect fatty acid metabolic fate through altered recognition by lipid metabolic enzymes. Although linoelaidic acid and petroselaidic acid followed distinct metabolic pathways, both converged on phospholipid remodeling that expanded pools of ferroptosis-susceptible membrane lipids. Together, our findings demonstrate that fatty acid double-bond geometry determines their metabolic fate and the membrane phospholipid composition, establishing lipid stereochemistry as a previously unrecognized structural determinant of ferroptosis sensitivity.

DOI: https://doi.org/10.64898/2026.07.17.739092
Nat Rev Drug Discov. 2026 Jul 28.

Prostaglandin E2 drives cancer-associated cachexia.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-026-00122-5
J Cell Biol. 2026 Oct 05. pii: e202510026. [Epub ahead of print]225(10):

Mechanical forces stimulate Golgi export.

Chandini Bhaskar Naidu, Javier Vera Lillo, Eugenia Almacellas, Anabel-Lise Le Roux, Sabine Bardin, Nicolas Mateos, Jessica Angulo-Capel, Adam Wolowczyk, Yugo Terashima, Yuichi Wakana, Pere Roca-Cusachs, Maria F Garcia-Parajo, Franck Perez, Bruno Goud, Jean-Baptiste Manneville, Stéphanie Miserey, Felix Campelo.

Cells face diverse mechanical stimuli that vary with cell type, state, and pathological conditions. Mechanobiology investigates how cells sense and respond to these forces. While most work has focused on the cell surface and nucleus as primary mechanosensors, how intracellular organelles adapt to extracellular mechanical forces remains largely unknown. Here, we show that extracellular mechanical signals influence the secretory function of the Golgi apparatus. By subjecting adherent cells to mechanical challenges-cell spreading on different ligands, altered substrate stiffness, or equibiaxial strain-we reveal that extracellular forces modulate Golgi-to-cell surface carrier biogenesis, thereby regulating exocytosis. Together with changes in Golgi membrane tension, we identify molecular determinants of the mechanotransduction pathway, including microtubule acetylation, diacylglycerol production, and protein kinase D activity. In turn, inhibition of Golgi export suppresses this mechanoresponse and causes impaired cell spreading. These findings uncover a bidirectional mechanotransduction axis in which extracellular mechanics tune Golgi secretory output, providing a framework for investigating organelle-based mechanoadaptation in physiology and disease.

DOI: https://doi.org/10.1083/jcb.202510026
Trends Cell Biol. 2026 Jul 31. pii: S0962-8924(26)00135-2. [Epub ahead of print]

Cellular lipid imaging at the ultrastructural level.

Fikadu G Tafesse, Carsten Schultz.

Lipids are fundamental organizers of biological membranes, yet visualizing lipid species within subcellular organelles has remained beyond experimental reach. Lennartz et al. introduce Lipid-correlative light and electron microscopy (CLEM), a CLEM workflow that maps lipid species onto membrane ultrastructure with nanoscale precision, uncovering active sphingomyelin sorting within the early endosome.

DOI: https://doi.org/10.1016/j.tcb.2026.07.002
Am J Physiol Cell Physiol. 2026 Jul 29.

Murine pancreatic tumors induce pathological remodeling of muscles critical to chewing and swallowing.

Sarah M Duckett, Jeremy B Ducharme, Martin M Schonk, Daria Neyroud, Sarah M Judge, Andrew R Judge.

  Cancer cachexia is a debilitating syndrome defined by involuntary weight loss due to loss of muscle mass, with or without loss of fat mass. Cachexia is particularly prevalent in pancreatic cancer, affecting up to 70% of patients at diagnosis, and is associated with reduced physical function, impaired treatment tolerance, and worsened survival. Skeletal muscle, including muscles involved in respiration and locomotion, exhibit extensive pathological remodeling in cachexia, including myofiber atrophy and transcriptional reprogramming. Whether muscles that are critical to chewing and swallowing respond similarly remains unknown. To address this gap, we collected masseter (chewing) and digastric (swallowing) muscles from cachectic mice bearing orthotopic KPC pancreatic tumors (n=8) and cancer-free Sham controls (n=8). Hematoxylin and eosin staining revealed increased mononuclear cell content, centralized nuclei, and expanded interstitial spaces in both muscles of KPC mice. Myofiber cross-sectional area was reduced by 42% in the masseter and 23% in the digastric. RNA sequencing revealed distinct transcriptional responses between these muscles. The masseter muscle showed enrichment of catabolic signaling pathways, including proteolytic and stress-response programs, alongside downregulation of extracellular matrix and growth-related programs. In contrast, the digastric muscle exhibited robust upregulation of immune and inflammatory pathways, including innate and adaptive immune signaling, with minimal overlap between muscles. Collectively, these findings demonstrate that pancreatic cancer drives pathological remodeling and atrophy in muscles central to chewing and swallowing while eliciting distinct, muscle-specific transcriptional responses, changes that could negatively affect food and nutrient intake and thereby contribute to cachexia progression.

Keywords:  cancer cachexia; digastric; masseter; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00390.2026
Biophys J. 2026 Jul 30. pii: S0006-3495(26)00537-0. [Epub ahead of print]

Coupling between sterol and sphingolipid structure in ordered membrane domains.

Israel Juarez-Contreras, Hyesoo Kim, Itay Budin.

A hallmark of eukaryotic membranes is the pairing of lineage-specific sterols with characteristic sphingolipid species. Mammalian cell membranes are enriched in both cholesterol and long-chain sphingolipids like sphingomyelin, whereas fungi synthesize ergosterol and very long-chain sphingolipids with sugar-containing head groups. It has been proposed that these two lipid classes co-evolved to support membrane structure and organization. Here we investigated how sterol structure and sphingolipid chain length together control membrane order and phase behavior. In the yeast Saccharomyces cerevisiae, loss of very long-chain C26 sphingolipids disrupted formation of liquid-ordered (Lo) domains in the vacuole membrane. Similarly, substitution of ergosterol synthesis for that of cholesterol also prevented vacuole Lo domains. To determine a possible physical basis of these effects, we investigated synthetic membranes of defined composition containing either ergosterol or cholesterol and sphingomyelin with different chain lengths. In membranes containing egg sphingomyelin with C16 chains, ergosterol only sparsely supported Lo domains, in contrast to cholesterol. Membranes containing sphingomyelin with C26 chains displayed a different pattern. Cholesterol mixtures were largely homogeneous across most compositions, with only a limited region that supported fluid domains. Ergosterol mixtures exhibited a distinct compositional window that supported fluid domains positioned between regimes of uniform membranes and gel phases. This window corresponded to lipidome changes in the vacuole as it phase separates during nutritional restriction. Measurements of membrane order showed that cholesterol strongly increased membrane packing compared to ergosterol in membranes containing egg sphingomyelin, whereas this difference was lost in membranes containing C26 sphingomyelin. The results suggest that sphingolipid chain length can tune sterol interactions needed for membrane organization.

DOI: https://doi.org/10.1016/j.bpj.2026.07.026
Cell Res. 2026 Jul 30.

Ferroptotic propagation: from single-cell execution to tissue-scale death programs.

Daolin Tang, Rui Kang, Guido Kroemer.

Ferroptosis has long been regarded as a cell-autonomous form of regulated cell death driven by iron-dependent lipid peroxidation. Recent work, however, suggests that ferroptotic commitment can extend beyond the initiating cell, spreading to neighboring cells and, in some contexts, across tissue-scale distances. Multiple, non-mutually exclusive modes of contagion have now been described, including reactive oxygen species-triggered death waves, direct membrane contact-dependent transfer, and extracellular vesicle-mediated paracrine signaling. These findings redefine ferroptosis from a single-cell execution pathway into a spatially coordinated, multicellular process. In this perspective, we integrate mechanistic insights with experimental evidence on ferroptotic contagion and propose a unifying, multiscale framework in which distinct modes of transmission operate over different spatial scales, from short-range membrane transfer to longer-range oxidative and extracellular relay mechanisms. We discuss how nonlinear redox amplification, membrane biophysics, and tissue architecture together determine the dynamics, limits, and patterning of ferroptotic injury in vivo. This emerging framework has important implications for developmental tissue remodeling, the progression of organ injury, and ferroptosis-based cancer therapy. More broadly, defining how ferroptotic contagion is initiated, constrained, and manipulated therapeutically may help establish ferroptosis as a fundamental organizing principle for understanding tissue-level regulation and pathological escalation.

DOI: https://doi.org/10.1038/s41422-026-01283-z
bioRxiv. 2026 Jul 24. pii: 2025.08.15.670583. [Epub ahead of print]

Multiple distinct metastatic cell states are induced by epithelial-mesenchymal plasticity.

Fahda Alsharief, Robert K Suter, Apsra Nasir, Idalia Cruz, Gray W Pearson.

Epithelial-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal-associated traits that can promote invasion and metastasis. Although distinct EMT-associated states have been linked to invasive and metastatic behavior, it remains unclear when these states arise during primary tumor progression, how they diversify, and whether metastatic competence is restricted to a particular EMT phenotype. Using single-cell RNA sequencing in a genetically engineered mouse model of triple-negative breast cancer (TNBC), together with functional studies of tumor organoids, we reconstructed the emergence of EMT-associated heterogeneity during tumor progression. We found that early malignant cells first lost mammary lineage identity, generating lineage-altered epithelial states with increased intrinsic plasticity. Rather than progressing through a single EMT program, these plastic states diversified through ERK1/2-low and ERK1/2-high EMT-associated programs. These programs generated distinct hybrid epithelial-mesenchymal states in early tumors and more uniform mesenchymal-like subpopulations at later stages, with canonical EMT features, diminished plasticity, and highly invasive behavior. Importantly, metastatic competence was not restricted to a single EMT-associated state: both heterogeneous hybrid cells and more uniform mesenchymal-like cells initiated metastases, with metastatic lesions retaining features of their initiating populations. Together, our results show that EMT-associated heterogeneity in TNBC emerges through early lineage-state disruption followed by parallel regulatory programs that generate distinct metastatic cell states rather than converging on a single highly metastatic phenotype.

DOI: https://doi.org/10.1101/2025.08.15.670583
Cell Rep. 2026 Jul 28. pii: S2211-1247(26)00829-6. [Epub ahead of print]45(8): 117751

Organelle proteomics of human, neonatal pig, healthy and diabetic mouse islets.

Özüm Sehnaz Caliskan, Daniel Thomas Haas, Joana Verissimo Ferreira, Sabina Chubanava, Elisabeth Kemter, Perla Cota, Aimée Bastidas-Ponce, Marta Tarquis-Medina, Oliver Czarnecki, Sreya Bhattacharya, Jessica Jaki, Verena Geiger, Pamela Kakimoto, Daniel Brandt, Magdalena Sachser, Carina Dürr, Hilda Delgado de la Herran, Alberto Cebrian-Serrano, Timo Dirk Müller, Eckhard Wolf, Heiko Lickert, Mostafa Bakhti, Natalie Krahmer.

  Pancreatic islets, in which β cells constitute 50%-80% of the endocrine mass, are the body's site for glucose-regulated insulin secretion. Pancreatic islet dysfunction is a hallmark of type 2 diabetes. Nevertheless, the molecular changes that impair their function remain insufficiently understood. To determine how islet cellular organization supports function and how it deteriorates in disease, we used machine learning-based organelle proteomics to build an organelle atlas of pancreatic islets from mice, humans, and pig neonatal islet-like cells. This cross-species resource maps localization of ∼8,000 proteins, revealing conserved organelle organization and identifying previously unrecognized components of insulin granules. Applying our organelle proteomics workflow to db/db mice, a T2D model uncovered disease-associated changes affecting vesicular trafficking and mitochondrial amino acid metabolism. Additionally, we found a disassembly of the insulin-granule acidification machinery. Our atlas provides insights into islet subcellular organization and identifies processes whose disruption may drive pancreatic islet failure in T2D.

Keywords:  CP: metabolism; CP: molecular biology; Organelle proteomics; V-type ATPase; beta cells; pancreatic islets; proline metabolism; type2 diabetes; vesicular trafficking

DOI:  https://doi.org/10.1016/j.celrep.2026.117751
Membranes (Basel). 2026 Jul 06. pii: 234. [Epub ahead of print]16(7):

A New Anatomy of Autophagic Clearance: On the Roles of Intrinsic Disorder in the Membrane-Less on Membrane-Encapsulated Mechanism.

Vladimir N Uversky, Hana Popelka, Daniel J Klionsky.

  Autophagy is a carefully regulated catabolic process that utilizes assemblies of specific sets of macromolecules operating at multiple stages of the pathway. Discoveries in recent years show that autophagy markedly relies on liquid-liquid phase separation (LLPS). Here, we present parameters that indicate the plasticity of autophagy proteins and their probability to undergo LLPS in macroautophagy and microautophagy. We show that microautophagy is an extremely LLPS-friendly pathway. Several mechanisms involving proteins in the autophagy machinery that drive LLPS on various types of membranes to regulate this process or that undergo LLPS as autophagic cargo are described in detail. We also summarize the factors that modulate the LLPS potential of autophagy proteins. A high probability of autophagy-related proteins to undergo spontaneous LLPS shown here can direct future research on the role of protein droplets in autophagy.

Keywords:  autophagy; intrinsically disordered protein; intrinsically disordered region; liquid-liquid phase separation; macroautophagy; microautophagy; posttranslational modification; protein1protein interaction

DOI:  https://doi.org/10.3390/membranes16070234
Nat Methods. 2026 Jul 31.

CellTune: an integrative software for accurate cell classification in spatial proteomics.

Yuval Bussi, Dana Shainshein, Eli Ovits, Sarah Posner, Nofar Azulay, Noa Maimon, Tal Keidar Haran, Raz Ben-Uri, Caitlin Brown, Noam Schuldiner, Eylon Yaniv, David Van Valen, Idan Milo, Ofer Elhanani, Robert Schiemann, Leeat Keren.

Spatial proteomics measures multiple proteins in situ, capturing tissue complexity. However, cell classification in densely packed tissues remains challenging because of the lack of efficient classification algorithms, annotation tools and high-quality labeled datasets to benchmark computational methods. We introduce CellTune, an integrated software for analysis of large spatial proteomics datasets, which streamlines precise cell classification through an optimized human-in-the-loop active learning workflow. It advances core capabilities for analysis of large datasets with an intuitive and code-free interface. To evaluate CellTune, we created CellTuneDepot, a resource of 40,000 manually annotated cells and 3.5 million high-quality labeled cells across 60 cell types. CellTune outperforms alternative methods, achieving accuracy comparable to human performance while enabling increased classification resolution and discovery of novel cell types. Together, CellTune and CellTuneDepot provide researchers with a tool for state-of-the-art classification accuracy and resolution at scale to drive biological insights.

DOI: https://doi.org/10.1038/s41592-026-03162-2
Nat Aging. 2026 Jul 30.

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.

Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.

DOI: https://doi.org/10.1038/s43587-026-01172-5
Nat Genet. 2026 Jul 31.

Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples.

Nicola Calonaci, Eriseld Krasniqi, Daniel Colic, Stefano Scalera, Giorgia Gandolfi, Salvatore Milite, Konstantin Bräutigam, Andrea Sottoriva, Trevor A Graham, Leonardo Egidi, Biagio Ricciuti, Marcello Maugeri-Saccà, Giulio Caravagna.

The interplay between somatic mutations and copy number alterations influences tumor evolution and prognosis. These alterations are often treated independently, overlooking gene mutant dosage (GMD)-a key property of their interaction. Here we develop a computational framework that infers mutation copy number and multiplicity from targeted sequencing panels without requiring matched normal samples. We derive GMD for over 500,000 mutations across 60,000 pan-cancer samples. By stratifying more than 20,000 patients according to GMD across multiple genes, we identify 46 tumor-type-specific biomarkers predictive of survival, 13 of which were undetectable using binary mutant/wild-type models, 26 were associated with metastatic spread and 20 predicted metastatic tropism. Our method reveals GMD patterns as independent predictors of disease prognosis, metastatic potential and site-specific dissemination across diverse tumor types. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis and holds the potential to substantially enhance biomarker discovery.

DOI: https://doi.org/10.1038/s41588-026-02666-z
bioRxiv. 2026 Jul 22. pii: 2026.07.21.739814. [Epub ahead of print]

Quantitative profiling of basal and stress-induced ribosome collisions.

James Marks, Pedro H Ayres-Galhardo, Bavavarshini Tamilselvam, Alexis Roberson, Ruby Pitts, Nicholas Guydosh, Sezen Meydan.

Ribosomes stall when they encounter problematic codons or cellular stress that perturbs translation. Stalled ribosomes can lead to the formation of ribosome collisions, also known as disomes, that engage cellular surveillance and stress signaling pathways. How many disomes form during basal conditions and how disome levels change under stress remain poorly understood. Here, we used spike-in normalized Ribo-seq and Disome-seq to quantify transcriptome-wide disome levels. Applying this approach in yeast and human cells, we found that disomes comprise approximately 2-10% of translating ribosomes under basal conditions. A high-resolution Disome-seq experiment in human cells identified reproducible disome-forming sites that contribute to the basal level of disome formation in the cell. Exposure of yeast cells to methyl methanesulfonate and human cells to anisomycin increased disome abundance up to four-fold and changed the distribution of collisions in a stress-specific and context-dependent manner. Overall, these data provide a quantitative, transcriptome-wide framework for measuring disome levels and reveal how translational stress reshapes the landscape of ribosome collisions in cells.

DOI: https://doi.org/10.64898/2026.07.21.739814
bioRxiv. 2026 Jul 19. pii: 2026.06.08.730907. [Epub ahead of print]

Oxidized protein states define metastatic fitness in lung cancer.

Maolin Ge, Magdy Gohar, Consuelo Torrini, Yukako Suzuki, Shan Jiang, Yuchen Huang, Benjamin Weinstein, Janice Wong, Naema Nayyar, Md Yousuf Ali, Emily Sullivan, Stefan Harry, Cagri Cakici, Zhuanglin Dai, Nicolò Vivori, Zhi Qiao, Junbing Zhang, Iphia Zhang, Connie Che, Reilly Stevens, Neha Khandelwal, Jinho Jeong, Yue Xu, Sufian Ibrahim, Haoqian Feng, Philipp Haehnel, Christopher W Mount, Maria Martinez-Lage, Lecia Sequist, Chendi Li, Sylvia Azer, Quan Lu, Fan-Yan Wei, Mario L Suvà, Brian B Liau, Aaron N Hata, Edward T Chouchani, A John Iafrate, Michael S Lawrence, Doga Gulhan, Priscilla K Brastianos, Liron Bar-Peled.

Reactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10•Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo . These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.

DOI: https://doi.org/10.64898/2026.06.08.730907
Cell Rep. 2026 Jul 31. pii: S2211-1247(26)00832-6. [Epub ahead of print] 117754

Microscale matrix defects suppress tension-dependent protrusions and stall collective cell migration.

Hannah Zmuda, Diego Barra Avila, Ping-Hsien Lee, Christopher Walter, Amit Pathak.

  During development, wound repair, and disease, epithelia must detect and respond to subtle extracellular defects to maintain coordinated migration. We show that collectively migrating epithelia undergo large-scale spatiotemporal stalling in response to laser-ablated micro-defects in the presence of collagen type IV. When the filopodia of leading-edge cells encounter micro-defects, the resulting local cytoskeletal disruption propagates to the follower cells, producing multicellular stalling over length scales much larger than the original defect. Extracellular changes in matrix stiffness, collagen type, and osmolarity regulate cell stiffness and membrane tension, which, in turn, control protrusive activity and stall migration. Through these extracellular variations, we found that stiffer cells and lower membrane tension suppress protrusions in leader cells, which enhances multicellular stalling through intercellular propagation of cytoskeletal disruption. This work advances the biophysical understanding of cell migration by showing that collagen-IV, softer matrices, and hypertonic media enhance cellular sensing of extracellular defects and wounds.

Keywords:  CP: Cell biology; basement membrane; cell stiffness; collagen; collective cell migration; extracellular matrix; mechanobiology; membrane tension

DOI:  https://doi.org/10.1016/j.celrep.2026.117754
bioRxiv. 2026 Jul 22. pii: 2026.06.25.734662. [Epub ahead of print]

Extravascular coagulation stabilizes pro-fibrotic stromal states via tumor-intrinsic PAR1 signaling in pancreatic ductal adenocarcinoma.

Sae Rome Choi, Natalia Ospina Munoz, Hye-Ran Moon, Sagar M Utturkar, Duy C K Do, Yun Chang, Xiaoping Bao, Abigail D Cox, Timothy L Ratliff, Claudius Conrad, Melissa L Fishel, Matthew J Flick, Nadia A Lanman, Bennett D Elzey, Bumsoo Han.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a desmoplastic stroma with context-dependent tumor-restraining and tumor-promoting functions, highlighting the need to selectively reprogram stromal states. Extravascular coagulation is a prominent feature of the PDAC tumor microenvironment, yet whether it functions as an upstream regulator of fibrotic stromal states, rather than merely a byproduct of tumor-associated vascular dysfunction, has remained unclear. Here, we identify extravascular coagulation as a tumor-amplified regulatory module that stabilizes pro-fibrotic stromal states via tumor-intrinsic protease-activated receptor-1 (PAR1) signaling. To interrogate this axis mechanistically, we combined human tumor bioinformatics with microphysiological tumor-stroma (MPTS) models and in vivo systems. Analysis of The Cancer Genome Atlas (TCGA) revealed heterogeneous F2R (PAR1) expression across tumors, with elevated expression associated with fibrotic transcriptional programs and reduced survival. Consistently, thrombin induced coordinated pro-fibrotic programs in tumor cells and cancer-associated fibroblasts (CAFs), which were recapitulated in microphysiological models where tumor-intrinsic PAR1 was required for amplification of extracellular matrix deposition and CAF activation. Mechanistically, PAR1 signaling amplified tumor-stroma communication, in part through induction of TGF-β1-dependent pathways, establishing a reinforcing feedback loop that stabilizes fibrotic remodeling. Pharmacologic inhibition of PAR1 selectively suppressed the fibrotic transcriptional program within myofibroblastic CAFs while reducing the abundance of other CAF subtypes, reprogramming stromal states and attenuating tumor progression across MPTS and in vivo models. These findings establish a coagulation-PAR1 axis as an upstream organizer of PDAC stromal architecture and identify pharmacologic PAR1 inhibition as a mechanistically grounded strategy for selectively reprogramming the tumor-promoting stroma.
Statement of Significance: Extravascular coagulation drives PDAC stromal fibrosis through tumor-intrinsic PAR1 signaling. Pharmacologic PAR1 inhibition selectively reprograms fibrotic CAF subtypes rather than depleting the stroma, offering a mechanistically grounded, therapeutically actionable strategy for PDAC.

DOI: https://doi.org/10.64898/2026.06.25.734662
EMBO Rep. 2026 Jul 30.

Cumulative microscopy reveals cellular states in fibroblasts from patients with genetic disorders.

Karen Akopyan, Zhiyu Hao, Susann Karlberg, Svetlana Vakkilainen, Fulya Taylan, Minna Pekkinen, Outi Mäkitie, Arne Lindqvist.

Analysis of cellular states and signaling trajectories can provide insights into causes of disease. We developed cumulative microscopy, a method to perform cyclical imaging without elution or quenching steps. Cumulative microscopy computationally extracts individual signals from accumulating fluorescence during sequential imaging. We use cumulative microscopy to quantitatively assess cell cycle and stress markers in individual primary fibroblasts from patients with rare genetic proliferative disorders with increased cancer risk. Neural network-based analysis of cumulative microscopy data suggests that cells from patients with Cartilage-hair hypoplasia (CHH), but not Mulibrey Nanism (MUL), show replication stress. We analyze cell states and cell trajectories and find that a subset of cells from patients with CHH show spontaneous replication stress, followed by cell cycle exit in both G1 and G2 phases. We note that replication stress potentially could underlie both proliferative defects and increased cancer risk in CHH patients and conclude that cumulative microscopy is an efficient, quantitative, and generalizable approach to multiplex microscopy.

DOI: https://doi.org/10.1038/s44319-026-00859-5
NPJ Metab Health Dis. 2026 Jul 29. pii: 29. [Epub ahead of print]4(1):

Timing the strain: skeletal muscle clock as regulator of physical activity.

Ippei Kawano, Gad Asher.

Skeletal muscle harbors cell-autonomous circadian clock that is implicated in muscle as well as systemic metabolic and physiological functions. Emerging evidence highlights how the muscle clock integrates time-signals to regulate physical activity. Physical activity imposes recurrent and temporally structured physiological and metabolic perturbations. Here we discuss the literature and propose that the muscle clock is well-positioned to execute anticipatory regulation by engaging metabolic programs in advance of predictable muscle demands.

DOI: https://doi.org/10.1038/s44324-026-00121-5
Cell. 2026 Jul 29. pii: S0092-8674(26)00814-7. [Epub ahead of print]

CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.

Alex C Y Chen, Keely Y Ji, Cansu Yerinde, Nelson H Knudsen, Kevin Bi, Shumeng Hao, Vasyl Zhabotynsky, Daniela Martinez, Thomas J Carmona-LaSalle, Kazuhiro Taguchi, Katherine H Xu, Elizabeth M Seider, Marc A Schwartz, Maria Zschummel, Linda T Nieman, Kathleen B Yates, Francesca S Gazzaniga, Brian C Miller, Thorsten R Mempel, Robert T Manguso, Nir Hacohen, Debattama R Sen.

  Immune aging impairs T cell-mediated tumor control as well as cancer immunotherapy outcomes. The most important drivers of T cell dysfunction in aged tumors remain unknown. We performed single-cell CRISPR screens to identify Dusp5 and Zfp219 as key regulators of CD8+ T cell persistence and effector differentiation within aged tumors. Loss of Dusp5 increased extracellular signal-regulated kinase (ERK) phosphorylation and globally enhanced T cell proliferation. Conversely, Zfp219 deletion induced epigenetic reprogramming and increased expression of cytotoxic molecules, enhancing antitumor immunity specifically in aging. Levels of the human ortholog ZNF219 were higher within intratumoral CD8+ T cells from older cancer patients, which correlates with worse survival following immunotherapy. Zfp219 ablation synergized with immune checkpoint inhibitors to expand effector-like CD8+ T cells, leading to tumor clearance in aged mice. Our findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction that can be targeted to rejuvenate antitumor immunity in older cancer patients.

Keywords:  T cells; antitumor immunity; cancer immunology and immunotherapy; immune aging; in vivo single-cell CRISPR screen

DOI:  https://doi.org/10.1016/j.cell.2026.07.016
Bio Protoc. 2026 Jul 20. 16(14): e5765

Actin Quantification Using the Filamentous Actin Segmentation Tool (FAST).

Vineeth Aljapur, Adam Gardner, Jason Carayanniotis, Andrew R Harris.

  Studying actin-filament assembly into distinct subcellular structures can provide insights into both physiological cellular processes and the mechanisms of disease. However, there are a limited number of tools that can quantify the organization and abundance of different actin structures from confocal microscopy images of cells expressing Lifeact or fixed and stained with phalloidin. Filamentous actin segmentation tool (FAST) is a deep learning model trained with a unique approach of antibody-assisted annotation, resulting in accurate and efficient quantification of distinct classes of actin structures. Here, we detail the protocol for using antibody-assisted annotation to generate datasets that could be applied to train machine learning models. Additionally, we provide step-by-step instructions for applying FAST on phalloidin-stained or live-cell confocal imaging data using our pretrained model. FAST is open source and freely available, with user-friendly notebooks that enable quantification of different classes of actin structure, without the need for structure-specific antibodies. As such, FAST can be a practical tool for researchers investigating the role of cytoskeletal organization in a range of processes. Key features • This antibody-assisted labeling approach can be used for identifying different classes of actin structure and generating labeled datasets for training machine learning algorithms. • The trained FAST model then enables the detection of distinct classes of actin structure without the need for multiple structure-specific antibodies. • FAST generates segmentation masks that can be used to quantify the abundance and organization of detected classes. • This protocol provides a graphical user interface for fine-tuning custom phalloidin-stained images and provides instructions on using trained model on Ilastik interface.

Keywords:  Actin; Cell segmentation; Confocal microscopy; Cytoskeleton; Deep learning; Fluorescence microscopy

DOI:  https://doi.org/10.21769/BioProtoc.5765
Biochim Biophys Acta Biomembr. 2026 Jul 25. pii: S0005-2736(26)00065-9. [Epub ahead of print]1868(4): 184562

The evolution of steady-state laurdan fluorescence: From model membranes to cellular applications.

Travis Issler, Evan Kerek, Elmar J Prenner.

  Laurdan (6-dodecanoyl-2-(dimethylamino)-naphthalene) is a solvatochromic fluorescent probe widely used for investigating membrane biophysical properties. Since its first application in phospholipid bilayers, laurdan has become a valuable tool in this field, owing to its sensitivity to the mobility and dynamics of surrounding lipid carbonyl groups and its ability to report on membrane phase behavior through the generalized polarization (GP) parameter. GP, a ratiometric empirical parameter, is derived from the ratio of emission intensities at approximately 440 and 490 nm, providing a measure of membrane fluidity ranging from rigid gel phases to more hydrated liquid-crystalline states. This review outlines the spectroscopic evolution of laurdan applications, beginning with steady-state fluorescence measurements in model membranes and progressing through more modern methodologies including anisotropy measurements, two-photon excitation microscopy, fluorescence correlation spectroscopy, and spectral phasor analysis. Key developments in laurdan's application to biological systems are discussed, including investigations of lipid raft-like domains, heavy metal-membrane interactions, and cellular membrane organization. Practical considerations for the exogenous incorporation of laurdan into membrane systems are also addressed, including the influence of solvent vehicle on probe aggregation and incorporation kinetics. Laurdan derivatives such as C-laurdan, CAPRYDAA, and organelle-targeted variants have further extended the versatility of this probe family. Together, these advances illustrate how laurdan has evolved from a simple polarity sensor into a multifaceted platform for characterizing membrane structure, lateral heterogeneity, and dynamics across model and biological systems.

Keywords:  Biological membranes; Generalized polarization; Laurdan; Membrane phase behaviour; Model systems

DOI:  https://doi.org/10.1016/j.bbamem.2026.184562
Cancers (Basel). 2026 Jul 14. pii: 2256. [Epub ahead of print]18(14):

Routes of Cancer Dissemination: Distinguishing Lymphatic and Hematogenous Spread from Venous Entry to Systemic Arterial Distribution.

Stanley P Leong.

  Background/Objectives: Cancer metastasis is responsible for most cancer-related deaths, yet the precise anatomical and physiological routes by which cancer cells disseminate remain incompletely defined. This review aims to present an integrated model of lymphatic and hematogenous dissemination that provides a unified framework for understanding metastatic progression. Methods: The published literature on lymphatic biology, microvascular physiology, tumor immunology, and cancer metastasis was critically reviewed and integrated to develop a comprehensive anatomical and physiological model of cancer dissemination. Results: The proposed model identifies lymphatic dissemination as the predominant metastatic route in many solid tumors. Cancer cells enter structurally permissive initial lymphatic capillaries and are transported to the sentinel lymph node (SLN), where interactions with the tumor microenvironment may eliminate disseminated cells, maintain dormancy, or facilitate immune escape and further dissemination. Cancer cells that survive within or escape beyond the SLN subsequently travel through collecting lymphatics and the thoracic or right lymphatic duct to enter the systemic venous circulation. Following cardiopulmonary transit, surviving cells may be redistributed through the systemic arterial circulation to distant organs. A secondary pathway involves direct hematogenous intravasation through post-capillary venules, where reduced shear stress, increased endothelial permeability, and permissive endothelial biology facilitate entry into the venous circulation. Thus, lymphatic and direct venular pathways ultimately converge in the venous circulation before systemic arterial dissemination. Conclusions: This unified model integrates lymphatic and hematogenous dissemination into a coherent anatomical and physiological framework. By emphasizing the SLN as an early immunologic checkpoint and the arterial circulation as the final distribution network for disseminated cancer cells, this review provides a conceptual basis for understanding metastatic patterns and identifying biomarkers and therapeutic vulnerabilities.

Keywords:  arterial circulation; cancer dissemination; cancer metastasis; hematogenous dissemination; lymphangiogenesis; lymphatic dissemination; organ tropism; post-capillary venules; pre-metastatic niche; sentinel lymph node (SLN)

DOI:  https://doi.org/10.3390/cancers18142256
J Biol Chem. 2026 Jul 30. pii: S0021-9258(26)02253-2. [Epub ahead of print] 113381

Sterol Flux Rewiring: Cholesterol Biosynthesis as a Dynamic Signaling Network.

Marc Poirot, Philippe de Médina, Sandrine Silvente-Poirot.

  Cholesterol biosynthesis is among the best-characterized metabolic pathways in biology, yet a fundamental question remains unresolved: why does this pathway generate more than twenty enzymatic reactions and numerous structurally distinct intermediates if cholesterol is its major biological end product? Over the past several decades, biochemical, genetic, pharmacological, biophysical, and lipidomic studies have progressively revealed that many sterol intermediates are not merely transient precursors. Instead, they possess distinct biophysical, signaling, and oxidative properties that contribute directly to cellular physiology and disease. However, these discoveries have largely been interpreted within separate biological and experimental contexts, including inherited disorders of cholesterol biosynthesis, membrane biology, nuclear receptor signaling, oxysterol metabolism, and pharmacological inhibition of distal sterol enzymes. Here, we propose that sterol flux rewiring provides an integrative framework that connects these independent observations into a unified view of cholesterol metabolism. In this framework, biological responses emerge from dynamic redistribution of metabolic flux, generating distinct sterol states characterized by specific membrane properties, signaling activities, oxidative potentials, and downstream metabolic outputs rather than by the accumulation of individual metabolites alone. This perspective explains how changes in sterol composition reshape membrane organization, oxidative diversification, and interconnected signaling networks, including the epoxycholestanoid pathway. It also provides a coherent framework for understanding how alterations in cholesterol metabolism contribute to development, immunity, neurobiology, ageing, regeneration, and cancer, while highlighting new opportunities for therapeutic strategies aimed at reprogramming sterol-state organization rather than simply inhibiting cholesterol synthesis.

Keywords:  Cancer metabolism; Cholesterol biosynthesis; EChA; oxysterols; sterol flux rewiring; sterol metabolism

DOI:  https://doi.org/10.1016/j.jbc.2026.113381
Chem Biomed Imaging. 2026 Jul 27. 4(7): 1352-1360

Nanoscale-Sensitive VSFG Microscopy for Identifying Breast Tumor in FFPE Samples.

Jianyu Ren, Chun-Chieh Yu, Aida Mestre-Farrera, Elizabeth A Pfau, Jing Yang, Wei Xiong.

  Nanoscale collagen remodeling is a critical physical signature of tumor development and metastasis. Recently, we have shown that vibrational sum-frequency generation (VSFG) microscopy can detect tumor tissues prepared from Optimal Cutting Temperature (OCT) samples, where this unique sensitivity to nanostructure comes from mode-specific coherent interference. Yet, most clinical tissues are processed as formalin-fixed, paraffin-embedded (FFPE) blocks, which remains unknown whether these harsh fixations and embedding processes destroy the subtle structural cues that VSFG detects. Thus, it could present a large barrier for further application of VSFG broadly into biophysics and biomedical research of tumors. Here, we demonstrate that VSFG remains fully effective in deparaffinized FFPE tissues. Crucially, following deparaffinization, key diagnostic metrics were statistically indistinguishable from OCT cryosection controls. These metrics included VSFG spectra, chemical images, and the collagen ratio I NHs /I CH2 ,Ss . Complementary atomic force microscopy (AFM) nanomechanics corroborated this finding. These findings open the path of using VSFG imaging for standard clinical workflows and the vast global archives of FFPE tissues for retrospective prognostic studies and label-free diagnostics.

Keywords:  Collagen organization; FFPE and OCT tissue; Human breast cancer; Label-free imaging; Tissue stiffness; Vibrational Sum-Frequency Generation (VSFG) microscopy

DOI:  https://doi.org/10.1021/cbmi.5c00240