bims-cagime 2026-08-09 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–08–09
29 papers selected by
Kıvanç Görgülü, Technical University of Munich

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.
Bioorthogonal Tools for Ethanolamine Lipids and Protein Conjugates.
Microenvironmental Prostaglandin F2α Antagonizes FSP1 in Cancer Cells to Sensitize Tumors to Ferroptosis and Immunotherapy.
CLOCK/BMAL1 interactome uncovers homeodomain factors as tissue regulators.
Spectral biophysical cytometry with nanosensors reveals remodelling of immune cells in atherosclerosis.
Spatially resolved tissue architecture and computational pathology in pancreatic cancer.
Editorial Expression of Concern: Tumour exosome integrins determine organotropic metastasis.
ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
Ferroptosis spreading through propagative signals.
Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes.
The microenvironment dictates glyco-immune surveillance via HSF1-mediated metabolism.
TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status.
A dependency map enhanced with next-generation 3D cancer models.
A compendium of next-generation patient-derived models for diverse cancers.
DCAF11-dependent molecular glue degrader activated by glutathionylation.
The Virtual Tissues foundation model resolves spatial proteomics across scales.
The effect of water stress on liquid ordered and liquid disordered phases of the lipid membrane: an atomistic comparison.
Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.
Broken chromosomes don't stay home: Tunneling nanotubes carry damaged DNA between human cells.
Lysosomal Profiling With LysoTracker For Quantitative Assessment of Cellular Senescence In Human Fibroblasts.
Charting intratumor heterogeneity from bench to bedside.
Tumoral extracellular vesicles and particles reprogram interstitial macrophages in the lung to promote vascular permeability and metastasis.
An ancient mitochondrial program tunes translation to haem availability.
How small can a cell be?
Daraxonrasib in pancreatic cancer: When progress disrupts practice.
Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.
A pipeline for quantifying cell damage in whole-slide fluorescence images of skeletal muscle.

Elife. 2026 Aug 05. pii: RP106492. [Epub ahead of print]14

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Lindsey N Dzierozynski, Chufan Cai, Leah M Ziolkowski, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

  Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

Keywords:  biochemistry; cancer; cancer biology; chemical biology; diet; human; metabolism; mouse; stress; synthetic lethality; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.106492
Nat Metab. 2026 Aug 05.

Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.

Anke Vandekeere, Juan Fernández-García, Yiming Peng-Winkler, Miguel Martín Pérez, Ming Liu, Sara Isabel Fernandes, Janine Theile, Philipp Willnow, Sanne Verheul, Gitte Zels, Anirudh Pabba, Christine Desmedt, Cornelis Verhoef, Patricia Altea-Manzano, Salvador Aznar Benitah, Ilaria Elia, Ilaria Malanchi, Sarah-Maria Fendt.

Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.

DOI: https://doi.org/10.1038/s42255-026-01582-0
Genes Dev. 2026 Aug 06.

Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.

Caleb Cheng, Rüya Pakkan, Arul M Chinnaiyan, Costas A Lyssiotis.

  Pancreatic ductal adenocarcinoma (PDAC) grows within a highly fibrotic, pressurized microenvironment that collapses vasculature and restricts delivery of oxygen and circulating nutrients. To survive this metabolic stress, PDAC cells activate lysosome-centered nutrient acquisition and recycling programs, including macroautophagy, RAS-driven macropinocytosis, and receptor-mediated endocytosis, that traffic intracellular and extracellular cargo to lysosomes for degradation and metabolite export. These pathways are reinforced by oncogenic signaling and MiT/TFE-dependent lysosomal biogenesis, and they support core outputs of tumor metabolism such as iron bioavailability, amino acid and nucleotide pools, lipid homeostasis, and immune evasion. Lysosomal programs in nonmalignant compartments (fibroblasts, stellate cells, and immune cells) further shape nutrient exchange, matrix production, and whole-body metabolism, positioning the lysosome as a key node at the tumor-host interface. Although genetic and pharmacologic blockade of autophagy/lysosome function can produce potent antitumor effects in preclinical models, clinical trials with lysosomotropic agents have shown limited benefit, highlighting challenges in target engagement, biomarkers, and rational combination strategies. Here we review current tools and concepts for interrogating lysosomal flux in PDAC, integrate emerging insights from systemic metabolism and dietary interventions, and outline therapeutic opportunities for more effectively exploiting lysosome dependence in pancreatic cancer.

Keywords:  lysosome metabolism; pancreatic cancer; tumor host metabolism

DOI:  https://doi.org/10.1101/gad.353702.126
Angew Chem Int Ed Engl. 2026 Aug 06. e1866870

Bioorthogonal Tools for Ethanolamine Lipids and Protein Conjugates.

Yuan-Ting Cho, Cindy Y Jao, Zijun Xia, Brittany M White-Mathieu, Adrian Salic, Jeremy M Baskin.

  Phosphatidylethanolamine (PE) is the second most abundant class of phospholipids in eukaryotic membranes, as well as a precursor for essential posttranslational protein modifications, such as PE conjugates of ubiquitin and ATG8/LC3 that play key roles in autophagy, and glycosylphosphatidylinositol (GPI) anchors of numerous cell surface proteins. Bioorthogonal chemistry has revolutionized how phospholipid biosynthesis, transport, and turnover are studied, with clickable metabolic precursors now available for several phospholipid classes. Yet no metabolic bioorthogonal probe for labeling endogenous PE and PE-derived protein modifications has been developed. Here, we introduce an alkyne-tagged ethanolamine analog (AlkEA) that is incorporated into PE via the Kennedy pathway and can be derivatized by copper-catalyzed azide-alkyne cycloaddition (CuAAC) for visualization and affinity enrichment. Confocal microscopy revealed the subcellular distribution of AlkEA-labeled PE in the ER, Golgi, mitochondria, and autophagosomes, while lipidomic analysis demonstrated AlkEA incorporation across diverse PE species. AlkEA labeling also allowed affinity isolation of PE-conjugated LC3 and ubiquitin, as well as that of a prototypical GPI-anchored protein. AlkEA is thus a minimally perturbing tool broadly applicable to dissecting PE metabolism and PE-dependent protein modifications.

Keywords:  bioorthogonal chemistry; click chemistry; imaging; lipid metabolism; lipidation; phospholipids

DOI:  https://doi.org/10.1002/anie.1866870
Cancer Res. 2026 Aug 06.

Microenvironmental Prostaglandin F2α Antagonizes FSP1 in Cancer Cells to Sensitize Tumors to Ferroptosis and Immunotherapy.

Yu Meng, Qian Zhou, Deze Zhao, Hui Su, Jiayuan Le, Daishi Li, Lei Yao, Ziyu Guo, Yixiao Xiong, Yuming Sun, Xiaowei Liang, Furong Zeng, Guangtong Deng, Xiang Chen.

Induction of ferroptosis is a potential strategy for treating cancer and improving the efficacy of immunotherapy. Ferroptosis is driven by excessive peroxidation of polyunsaturated fatty acid-containing phospholipids, suggesting that microenvironmental lipid metabolites may regulate ferroptotic sensitivity. By integrating single-cell and bulk transcriptomics from immunotherapy cohorts, we identified the prostaglandin (PG) pathway as closely associated with tumor ferroptosis and therapeutic efficacy. Further screening revealed PGF2α as a potent endogenous ferroptosis sensitizer. Mechanistically, microenvironmental PGF2α bound to ferroptosis suppressor protein 1 (FSP1) at alanine 295 (A295) and inhibited its enzymatic activity, leading to lipid peroxidation accumulation upon ferroptotic stimuli. Preclinically, PGF2α supplementation or FSP1 ablation enhanced tumoral ferroptosis, potentiated CD8+ T cell-mediated immunity, and suppressed tumor progression in immunocompetent mice. Moreover, PGF2α improved immunotherapy efficacy across multiple mouse models, including subcutaneous allografts, Braf/Pten-driven spontaneous melanoma, and humanized mice. Clinically, a high PGF2α activity-related transcriptomic signature correlated with elevated ferroptosis and improved patient survival. Collectively, these findings establish PGF2α as a pro-ferroptotic metabolite and propose that targeting the PGF2α/FSP1 axis may offer an effective cancer immunotherapeutic strategy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5697
Nat Cell Biol. 2026 Aug 06.

CLOCK/BMAL1 interactome uncovers homeodomain factors as tissue regulators.

Fatih Aygenli, Lukas A Huschet, Tanja Popp, Andrea Ribeiro, Darina Barkhatova, Céline Jouffe, Ricardo Trozzo, Jerome S Menet, Roland Rad, Kenneth A Dyar, Maciej Lech, Tobias Straub, Alicia K Michael, Maria S Robles.

Circadian clocks underlie daily rhythms in physiology by coordinating temporal patterns of gene expression and protein function throughout the body. At the core of this system in mammals is CLOCK/BMAL1, a ubiquitously expressed heterodimeric transcription factor complex that orchestrates tissue-specific circadian gene expression. The basis for this specificity remains unclear, but tissue-specific interactions at chromatin could provide one. Here we used chromatin immunoprecipitation coupled to mass spectrometry to map CLOCK/BMAL1-associated protein complexes on chromatin in mouse liver, kidney and lung. We detected 1,510 associated proteins, most of which were tissue-specific and not explained by protein abundance. Among these, we identified the homeodomain transcription factors PROX1, HNF1B and HOXA5 as tissue-enriched interactors that bind BMAL1, co-occupy most BMAL1 genomic sites and establish organ-restricted circadian transcription. Our findings demonstrate that tissue-specific transcription factors confer cellular identity on the core clock, thereby contributing to organ-specific patterns of rhythmic gene expression.

DOI: https://doi.org/10.1038/s41556-026-02041-4
Nat Nanotechnol. 2026 Aug 06.

Spectral biophysical cytometry with nanosensors reveals remodelling of immune cells in atherosclerosis.

Cenk O Gurdap, Dunya Aydos, Luca A Andronico, Gábor Tóth, Tugce Ceker, John Cowgill, Irem Muge Akbulut Koyuncu, Neslihan Basak, Jaromir Mikes, Andrey S Klymchenko, Federico Pietrocola, Petter Brodin, Ingela Lanekoff, Verda Ceylan Bitirim, Erdinc Sezgin.

The biophysical properties of cells determine cellular physiology. Leveraging these properties for biomedical applications demands the ability to measure multiple parameters simultaneously across millions of cells and diverse cell types. However, current technologies are limited by throughput and low dimensionality. Here we introduce spectral biophysical cytometry (SBC), a high-throughput platform that integrates environment-sensitive nanosensors with spectral flow cytometry to resolve multiparametric biophysical properties of immune cells at single-cell resolution. By using fluorescent nanosensors that report membrane order, mitochondrial potential and membrane potential, SBC enables simultaneous quantification of key cellular physical states across diverse immune cell populations. When applied to peripheral blood mononuclear cells, SBC reveals cell-type-specific biophysical heterogeneity and identifies distinct remodelling signatures associated with atherosclerosis. In particular, T-cell subsets exhibit substantial alterations in membrane order and mitochondrial depolarization, reflecting coordinated changes in lipid composition and metabolic pathways. Integration with lipidomics and transcriptomics demonstrates that the nanosensors can detect biophysical shifts that correlate with dysregulated lipid metabolism and mitochondrial function, providing mechanistic insight into immune dysfunction in disease. Importantly, SBC achieves rapid, label-efficient profiling using commercially available instrumentation, enabling scalable biomarker discovery directly from blood samples and establishing a powerful strategy for linking biophysical phenotypes to immune cell function.

DOI: https://doi.org/10.1038/s41565-026-02236-8
Exp Mol Med. 2026 Aug 04.

Spatially resolved tissue architecture and computational pathology in pancreatic cancer.

Seong-Woo Bae, Aristotelis Tsirigos, Jimin Min, Anirban Maitra.

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease characterized by high levels of cellular heterogeneity and pronounced microenvironmental remodelling. Dynamic changes during its initiation and progression contribute to resistance to conventional therapies. Building upon key molecular catalogues established by bulk and single-cell profiling studies that have advanced our understanding of PDAC biology, recent advances in spatial biology have provided much-needed insights by elucidating regionally compartmentalized transcriptomic and proteomic programmes within the PDAC microenvironment. In parallel, emerging computational frameworks in digital pathology and artificial intelligence have advanced the field into a high-dimensional, quantitative discipline, particularly for classifying molecular and clinical features from histopathology images. Despite these advancements, integration of these two modalities remains a major challenge. Here, we summarize the convergence of molecular features identified through spatially resolved profiling in PDAC and its precursor lesions, as well as current developments in AI-powered pathology in cancer research. We further propose a multi-modal integration framework that maps molecular states onto morphological and architectural phenotypes, offering a roadmap for spatially informed patient stratification beyond descriptive tissue characterization. We posit that the path forward relies on disciplined cross-scale integration of spatial, histological, and clinical data to ensure meaningful translation into clinical practice.

DOI: https://doi.org/10.1038/s12276-026-01782-4
Nature. 2026 Aug 05.

Editorial Expression of Concern: Tumour exosome integrins determine organotropic metastasis.

Ayuko Hoshino, Bruno Costa-Silva, Tang-Long Shen, Goncalo Rodrigues, Ayako Hashimoto, Milica Tesic Mark, Henrik Molina, Shinji Kohsaka, Angela Di Giannatale, Sophia Ceder, Swarnima Singh, Caitlin Williams, Nadine Soplop, Kunihiro Uryu, Lindsay Pharmer, Tari King, Linda Bojmar, Alexander E Davies, Yonathan Ararso, Tuo Zhang, Haiying Zhang, Jonathan Hernandez, Joshua M Weiss, Vanessa D Dumont-Cole, Kimberly Kramer, Leonard H Wexler, Aru Narendran, Gary K Schwartz, John H Healey, Per Sandstrom, Knut Jørgen Labori, Elin H Kure, Paul M Grandgenett, Michael A Hollingsworth, Maria de Sousa, Sukhwinder Kaur, Maneesh Jain, Kavita Mallya, Surinder K Batra, William R Jarnagin, Mary S Brady, Oystein Fodstad, Volkmar Muller, Klaus Pantel, Andy J Minn, Mina J Bissell, Benjamin A Garcia, Yibin Kang, Vinagolu K Rajasekhar, Cyrus M Ghajar, Irina Matei, Hector Peinado, Jacqueline Bromberg, David Lyden.

DOI: https://doi.org/10.1038/s41586-026-10977-8
Nature. 2026 Aug 05.

ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.

Qingwen Jiang, Manisha S Raghavan, Aileen M Rodriguez, Morgan Lallo, Cyrus L Tam, Saskia Hartner, Britney Forsyth, Ahmed Mahmoud, Fabian Zincke, Huiyong Zhao, Andrew Moorman, Sasha Balkaran, Kathleen Luckett, Jura Pintar, Yevgeniy Romin, Eric Chan, Anthony Santella, Bernadette Mödl, Farheen Shah, Ilyes Baali, Michael G Kharas, Elisa de Stanchina, Nil Urganci, Jinru Shia, Dana Pe'er, Francisco Sanchez-Vega, Richard Koche, Quaid Morris, Joseph M Chan, Karuna Ganesh.

Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.

DOI: https://doi.org/10.1038/s41586-026-10890-0
EXO. 2026 ;pii: 202613. [Epub ahead of print]1(2):

Ferroptosis spreading through propagative signals.

Saloni K Hombalkar, Jyotirekha Das, Michael Overholtzer.

  Ferroptosis is a regulated mechanism of cell death caused by the uncontrolled peroxidation of cellular lipids that has an unusual ability to propagate or spread between cells. Here, we review studies identifying regulators of ferroptosis propagation to consider a working model that might explain this unusual feature. Recent findings implicating the spread of lipid peroxides and iron suggest that these main catalysts of ferroptosis may also be primary vehicles that can spread death between cells. Experiments revealing localized versus long-range effects of propagation are discussed, as well as sensitizing factors that may expand the propagative potential of death induced by Class II ferroptosis-inducing compounds. As ferroptosis propagation may underlie the loss of large groups of cells in degenerative diseases and may also have a specialized role in normal development, consideration of how ferroptosis can spread through propagative signals may be important for understanding both normal tissue dynamics and disease.

Keywords:  Ferroptosis; erastin; ferritin; glutathione peroxidase 4; iron; lipid peroxidation; lysosome; propagation

DOI:  https://doi.org/10.70401/EXO.2026.0011
Genes Dev. 2026 Aug 06.

Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes.

Elisa Gomez-Gil, Paolo Guerra, Ying Gu, Sherman Foo, Benedicte Billard, Gabor Balogh, Maria Peter, Snezhana Oliferenko.

  The physicochemical properties of biological membranes must be maintained within a range compatible with cellular physiology. In the face of external perturbations, membrane lipid homeostasis mechanisms sense and control membrane features. How such mechanisms evolve to function in organisms with different cellular lipid make-up is unknown. Here, we address this fundamental question by exploiting the natural divergence in membrane lipid composition between the related fission yeasts Schizosaccharomyces pombe and Schizosaccharomyces japonicus Using lipidomics and transcriptomics, we show that the activity of the membrane-bound transcriptional activator Mga2, which regulates the Δ-9 desaturase Ole1 expression, is set to sense distinct levels of membrane unsaturation in the two species. Through retroengineering and physiological experiments, we identified an evolutionary divergent but functionally constrained element within the juxtamembrane region of Mga2, which fine-tunes its performance to species-specific lipid composition. Our experiments indicate that high baseline expression of ole1, set by cis-regulatory elements in its upstream noncoding region, has redefined the dynamic range of Mga2 activation in S. pombe, supporting high lipidome unsaturation. Our work explores an "experiment of nature" to highlight the broad principles underlying the organization and evolution of membrane homeostasis, which should be applicable to other genetic networks supporting cellular homeostatic processes.

Keywords:  evolution; fission yeasts; homeostasis; membrane

DOI:  https://doi.org/10.1101/gad.353500.125
Sci Adv. 2026 Aug 07. 12(32): eaeb1136

The microenvironment dictates glyco-immune surveillance via HSF1-mediated metabolism.

Kevin M Tharp, Sangwoo Park, Greg A Timblin, Alicia L Richards, Jordan A Berg, Nicholas M Twells, Nicholas M Riley, Kyle Alvarez, Allen Lee, Egan L Peltan, D Judy Shon, Erica Stevenson, Kimberly Tsui, Francesco Palomba, Austin E Y T Lefebvre, Ross W Soens, Jaya L Thangaraj, Nadia M E Ayad, Joseph A Rhodenhiser, Johanna Ten Hoeve, Kevin Healy, Michelle Digman, Andrew Dillin, Nevan J Krogan, Carolyn R Bertozzi, Dan S Kaufman, Sanju Sinha, Danielle L Swaney, Lara K Mahal, Jason R Cantor, Matthew J Paszek, Valerie M Weaver.

Altered glucose metabolism is an auspicious feature of solid tumors, but is it an intrinsic property of tumor cells or a metabolic adaptation to the tumor microenvironment? Using normal epithelial cells cultured in a physiological culture medium under conditions that mimic the physical properties of healthy or cancerous tissues, we establish multiomics relationships between the biochemical and physical properties of the microenvironment and its impact on biosynthetic outputs of altered glucose metabolism. We find that microenvironmental properties, such as hyperglycemia, can affect the composition and thickness of the epithelial glycocalyx, in part through the activity of mechanosensitive stress responses associated with Heat Shock Factor 1 (HSF1). Because glycocalyx thickness alters immune surveillance of epithelial-origin tumor cells, we examined the relationship between the HSF1-hyperglycemia axis in human breast tumors and validate it as a druggable vulnerability to license natural killer cell lethality against cancer cells.

DOI: https://doi.org/10.1126/sciadv.aeb1136
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2602941123

TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status.

Rebecca Deutsch, Simone Jörs, Yvonne Klingl, Veronika Kudrina, Danusa Menegaz, Dawid Jaślan, Zala Serianz, Andreas Vogel, Carla Abrahamian, Sayari Bhunia, Tinatini Tavhelidse-Suck, Christin Richter, Angela Wirth, Nicole Urban, Bernd Northoff, Wolfgang Wilfert, Norbert Klugbauer, Franz Bracher, Marco Keller, Fabian Geisler, Michael Schaefer, Daniel Teupser, Lesca Holdt, Serkan Belkaya, Marc Freichel, Christian Grimm.

  Iron overload is a life-threatening disease. Without early diagnosis and treatment, it can cause severe organ damage and even premature death by irreversibly damaging organs such as the heart, pancreas, spleen, or liver. We report here that a gain-of-function mutation in the endolysosomal two-pore channel TPC1 (TPC1I486T) causes iron overload in mice, whereas mice lacking TPC1 exhibit the opposite phenotype, iron deficiency. Endolysosomal patch-clamp experiments demonstrated a strong gain in both human and mouse TPC1 mutant channel activity compared to wild-type upon activation with the early endosome (EE) associated endogenous ligand phosphatidylinositol 3-phosphate. Mechanistically, it was found that uptake of iron bound to transferrin/transferrin receptor from the plasma membrane as well as the pH in EE, from where Fe2+ is being released via DMT1 in a H+ dependent manner strongly depend on TPC1 activity.

Keywords:  TPC; TPC1; TPCN1; endosome; iron

DOI:  https://doi.org/10.1073/pnas.2602941123
Nature. 2026 Aug 05.

A dependency map enhanced with next-generation 3D cancer models.

James V Neiswender, Samuel Maffa, Lisa Brenan, Dina ElHarouni, Yejie Yun, Isabella Boyle, Kirsty Wienand, Haider Inam, Tate Bertea, Ashley Anderson, Megan Wong, Matias Enriquez, Evan Lenz, Beatriz Villafranca, Nora Shanks, Mary Hager, Nia Lloyd, Hannah Shadmany, Sarah J Wie, Harry Liang, Konnor Yunghans, Xiaomeng Zhang, Lauren Golden, Hannah Harris, Serena Day, Philip Montgomery, Samantha Stokes, Ross M Giglio, Cynthia Hajal, James R Whittle, Guadalupe Garcia, Caitlin E Mills, Mehdi Touat, Kristine Pelton, Hongyu Li, Prem Sai Prabhakar, Sonja Herter, Zoe Hoffmann Kamrat, Dan Gui, Julien Dilly, Chen Khuan Wong, Jimmy A Guo, Sangita Pal, Yossef Baidi, Ryan Johnston, Daniel D Brown, Sonam Bhatia, Peter S Winter, Srivatsan Raghavan, Rameen Beroukhim, Eva Colas, David L Spector, Adam J Bass, Peter K Sorger, Yu Chen, Sarah J Hill, Steffi Oesterreich, Adrian V Lee, Himisha Beltran, Jesse S Boehm, Yuen-Yi Tseng, David E Root, William C Hahn, Andrew J Aguirre, Catarina D Campbell, Keith L Ligon, Joshua M Dempster, Tsukasa Shibue, Francisca Vazquez.

Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over 1,300 cell lines have led to the discovery of new therapeutic strategies across multiple tumour types2. However, mapping cancer vulnerabilities using traditional cell lines has limitations, including insufficient cancer subtype representation and the impact of culture conditions on perturbation responses. Here we perform 147 genome-scale CRISPR screens and multi-omic characterizations of next-generation (NextGen) cancer models (organoids and spheroids) across 10 cancer types. This strategy enables the expansion of DepMap to cover new genomic and molecular subtypes and to identify new biomarker-associated vulnerabilities. These new models also preserve transcriptional programs that are silenced in traditional cell lines and facilitate the discovery of specific gene dependencies associated with these programs. Comparisons of traditional and NextGen cancer models enable further identification of distinct effects of growth format and culture medium on gene essentiality. The integrated dataset combines data from both model types to offer a valuable, expansive resource for exploring cancer vulnerabilities and is accessible via the DepMap portal.

DOI: https://doi.org/10.1038/s41586-026-10843-7
Nature. 2026 Aug 05.

A compendium of next-generation patient-derived models for diverse cancers.

HCMI Network

The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.

DOI: https://doi.org/10.1038/s41586-026-10806-y
Nature. 2026 Aug 05.

DCAF11-dependent molecular glue degrader activated by glutathionylation.

Hojong Yoon, Franziska Wachter, Katharine A Barrett, Cyrus Jin, Anna Rodríguez-Pöhnlein, Justine C Rutter, Ryan J Lumpkin, Rebecca J Metivier, Katherine A Donovan, Kheewoong Baek, Yongying Jiang, Minwoo Lee, Robert W Kalis, Jianwei Che, Yuan Xiong, Eric S Fischer, Benjamin L Ebert.

Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.

DOI: https://doi.org/10.1038/s41586-026-10873-1
Nature. 2026 Aug 05.

The Virtual Tissues foundation model resolves spatial proteomics across scales.

Johann Wenckstern, Eeshaan Jain, Benedikt von Querfurth, Yexiang Cheng, Kiril Vasilev, Matteo Pariset, Phil F Cheng, Petros Liakopoulos, Olivier Michielin, Andreas Wicki, Gabriele Gut, Charlotte Bunne.

Spatial proteomics technologies have transformed our understanding of complex tissue architecture in cancer but present unique challenges for computational analysis1. Each study uses a different marker panel and protocol, and most methods are tailored to single cohorts, which limits knowledge transfer and robust biomarker discovery. Here we present Virtual Tissues (VirTues), a general-purpose foundation model for spatial proteomics that learns marker-aware, multi-scale representations of proteins, cells, niches and tissues directly from multiplex imaging data. From a single pretrained backbone, VirTues supports marker reconstruction, cell segmentation and typing, niche annotation, spatial biomarker discovery and patient stratification, including zero-shot annotation across heterogeneous panels and datasets. In triple-negative breast cancer, VirTues-derived biomarkers predict anti-PD-L1 chemo-immunotherapy response2 and stratify disease-free survival in an independent cohort3, outperforming state-of-the-art biomarkers derived from the same datasets and current clinical stratification schemes.

DOI: https://doi.org/10.1038/s41586-026-10884-y
Phys Chem Chem Phys. 2026 Aug 05.

The effect of water stress on liquid ordered and liquid disordered phases of the lipid membrane: an atomistic comparison.

Abhay Kumar, Snehasis Daschakraborty.

Understanding how biological membranes retain integrity under extreme dehydration is vital for explaining anhydrobiotic survival and defining the physicochemical limits of life. Here, we use molecular dynamics simulations to investigate how progressive dehydration (30-2 water molecules per lipid) affects a liquid-disordered (Ld) DPPC/DOPC/cholesterol membrane. Dehydration reduces the area per lipid and membrane thickness, increases acyl-chain ordering, and majorly suppresses membrane lateral diffusion, with trends comparable to those observed in the liquid-ordered (Lo) phases, indicating a largely phase-independent response. The hydrogen-bond analysis shows that the phosphate-associated oxygen atoms retain the strongest and most persistent interactions, maintaining nearly constant free energy of bond disruption and thereby stabilizing the lipid membrane. Overall, both the Ld and Lo lipid membranes rely on localized head group hydration to withstand water loss, offering molecular insight into lipid membrane resilience in anhydrobiosis, extremophile biology, and water-limited environments.

DOI: https://doi.org/10.1039/d6cp01676f
Autophagy. 2026 Aug 06. 1-17

Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.

F Abrar, D D O Martin.

  SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.

Keywords:  Neuroscience; S-acylation; p62; post-translational modifications; sequestosome 1

DOI:  https://doi.org/10.1080/15548627.2026.2711593
Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00469-7. [Epub ahead of print]86(15): 2897-2899

Broken chromosomes don't stay home: Tunneling nanotubes carry damaged DNA between human cells.

Francesca Palese, Chiara Zurzolo.

In a recent Cell paper, Maurais et al.1 show that genomic instability drives human cells to transfer fragmented chromosomes to neighbors via tunneling nanotubes (TNTs), with heritable functional consequences, raising fundamental questions about intercellular communication, genome surveillance, and cancer evolution.

DOI: https://doi.org/10.1016/j.molcel.2026.07.005
J Vis Exp. 2026 Jul 17.

Lysosomal Profiling With LysoTracker For Quantitative Assessment of Cellular Senescence In Human Fibroblasts.

Javier Estrada Toro, Scott A Tenenbaum, Melinda Larsen, Thomas J Begley, J Andres Melendez.

Cellular senescence is a stable cell-cycle arrest state associated with characteristic phenotypes, including enlarged cell morphology, altered secretory signaling, and pronounced lysosomal remodeling. Senescent cells commonly exhibit expansion of the acidic endo-lysosomal compartment, accompanied by changes in luminal acidity and degradative capacity, creating an opportunity for simple live-cell readouts of senescence-linked organelle remodeling. This work describes a live-cell imaging protocol that uses LysoTracker Deep Red, an acidotropic fluorescent dye, to provide an indirect, pH-dependent proxy for the acidic organelle compartment as a correlate of senescence burden. The method is demonstrated in IMR-90 human lung fibroblasts undergoing replicative senescence across serial passaging. The protocol details cell culture and passage tracking, LysoTracker staining, fluorescence imaging, and image-based quantification of lysosomal signal intensity and signal-positive area per cell. Senescence-associated β-galactosidase (SA-β-Gal) staining on parallel cultures is included as an optional confirmatory marker rather than a reference standard. Representative outcomes show higher acidotropic fluorescent dye signal and larger lyso-positive regions in late-passage cultures than in early-passage controls, consistent with expansion of the acidic organelle compartment during senescence. Because the readout depends on compartment volume, proton gradient, and dye availability, it is best interpreted as an indirect correlate of lysosomal remodeling rather than a direct measure of lysosome number or biogenesis. The protocol is simple to adopt and can be adapted to other cell types or senescence-inducing stresses, providing a practical, quantitative complement to conventional endpoint assays.

DOI: https://doi.org/10.3791/70684
Nat Cancer. 2026 Aug 07.

Charting intratumor heterogeneity from bench to bedside.

Jonathan C M Wan, Nicholas McGranahan, Charles Swanton.

Intratumor heterogeneity poses a fundamental challenge across the cancer care continuum, from diagnosis to treatment resistance and metastasis. Over recent decades, multiregion and multiomic profiling of tissue, together with functional studies and longitudinal plasma sampling, have revealed the dynamic and multidimensional evolution of tumor ecosystems. This complexity spans genetic and non-genetic mechanisms within cancer cells and their microenvironment. In this Review, we synthesize the current understanding of heterogeneity and evolution and discuss how these insights can inform the development of evolution-aware diagnostic and therapeutic strategies.

DOI: https://doi.org/10.1038/s43018-026-01198-z
Nat Cancer. 2026 Aug 05.

Tumoral extracellular vesicles and particles reprogram interstitial macrophages in the lung to promote vascular permeability and metastasis.

Shani Dror, Inbal Wortzel, Serena Lucotti, Yura Seo, Jianlong Li, Lee Shaashua, Irina Matei, Nancy Boudreau, Haiying Zhang, Maider Astorkia-Amiama, Doron Betel, Han Sang Kim, Jai Prakash, Jacqueline Bromberg, David Lyden.

The mechanisms by which tumor-derived extracellular vesicles and particles (EVPs) promote vascular permeability during premetastatic niche formation remain unclear. Here, we show that tumor EVPs rapidly induce vascular leakiness within 1 h of administration in female mice, creating a permissive environment that enhances metastatic seeding. Rather than acting directly on endothelial cells, EVPs activate NF-κB and JAK-STAT signaling in interstitial macrophages, leading to IL-6 secretion and increased vascular permeability. Interstitial macrophage depletion markedly reduces EVP-induced vascular leakiness and metastasis. We identify extracellular vesicle-associated integrin α5 (ITGα5) as a major functional determinant of this process, promoting macrophage activation and IL-6 secretion without affecting EVP uptake. EVPs derived from colorectal cancer tumors with high ITGα5 similarly induce macrophage IL-6 secretion and vascular permeability. Together, these findings define an EVP-macrophage-IL-6 axis that drives vascular permeability during premetastatic niche formation and identify EVP-associated ITGα5 as a key mediator of metastatic progression and a potential therapeutic target.

DOI: https://doi.org/10.1038/s43018-026-01209-z
Nature. 2026 Aug 05.

An ancient mitochondrial program tunes translation to haem availability.

Xiang Zhang, Max-Hinderk Schuler, Gonca Çetin, Eva-Maria Eckl, Lara Rheinemann, Julia Mergner, Barbara Steigenberger, Andreas Pichlmair, Lucas T Jae.

Anaemia is a major global health burden that affects one-quarter of the human population and annually accounts for over 50 million years of healthy life lost1. It arises from nutritional iron deficiency, hereditary disorders (including thalassaemia and sickle cell disease) and malaria, and is characterized by haemoglobin imbalances2. Haem-the active component of haemoglobin-is both essential and potentially toxic, which necessitates tight control of levels. However, the molecular circuitry that monitors haem levels remains obscure. The cytosolic eIF2α kinase HRI counteracts anaemia amid iron deficiency or thalassaemia3,4 by acting as a gatekeeper of translation during erythroid differentiation, which has been attributed to its haem-binding ability5. Here we uncover that haem scarcity is sensed inside mitochondria through an OMA1-DELE1 axis. Mechanistically, haem deficiency triggers OMA1-dependent mitochondrial release of DELE1. In the cytosol, DELE1 releases inhibitory haem from HRI, which enables modifications in a crucial disordered segment of the kinase. We demonstrate that this sensor-actuator operates across human tissues, including erythroid progenitors, and is evolutionarily conserved down to bloodless invertebrates, thus predating the emergence of haemoglobin-based oxygen transport. Notably, pharmacological manipulation of this system enhances fetal globin expression-a central therapeutic objective in haemoglobinopathies. Together, these results reveal a primordial sentinel system that safeguards against haem-related toxicity from the single-cell to the organismic scale.

DOI: https://doi.org/10.1038/s41586-026-10885-x
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2619024123

How small can a cell be?

Shicong Xie, Jan M Skotheim.

DOI: https://doi.org/10.1073/pnas.2619024123
Drug Discov Today. 2026 Aug 07. pii: S1359-6446(26)00166-2. [Epub ahead of print] 104761

Daraxonrasib in pancreatic cancer: When progress disrupts practice.

Asfar S Azmi, Philip A Philip.

DOI: https://doi.org/10.1016/j.drudis.2026.104761
Cell Rep Med. 2026 Aug 06. pii: S2666-3791(26)00393-9. [Epub ahead of print] 102976

Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.

Jiatong Li, Ao Gu, Ziheng Jia, Mengyao Li, Jinlu Zuo, Ziyi Wang, Xuechuan Li, Jiayi Feng, Tong Xue, Shuyang Zhai, Zhuying Yue, Yang An, Siyuan Kang, Zhiqing Yuan, Shimei Qiu, Yadong Xue, Liguo Liu, Nannan Tang, Yingbin Liu.

  Approximately 90% of patients with pancreatic cancer harbor KRAS mutations, predominantly the KRASG12D subtype. HRS-4642, a non-covalent inhibitor targeting KRASG12D, demonstrates potent antitumor efficacy but may ultimately lead to resistance. This study investigates the mechanisms underlying KRASG12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRASG12D inhibitor resistance in pancreatic ductal adenocarcinoma (PDAC) but also achieves remission with prolonging survival. Mechanistically, KRASG12D inhibitor resistance markedly upregulates ANXA1 expression, which, in turn, promotes its binding to the glutamine-related enzyme GOT1 and stabilizes its expression. Additionally, we find that ANXA1 upregulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRASG12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRASG12D mutant PDAC.

Keywords:  ANXA1; KRAS-G12D inhibitors; PDAC; drug resistance; glutamine

DOI:  https://doi.org/10.1016/j.xcrm.2026.102976
Methods. 2026 Aug 06. pii: S1046-2023(26)00170-2. [Epub ahead of print]

A pipeline for quantifying cell damage in whole-slide fluorescence images of skeletal muscle.

Marisa Sargent, Alastair W Wark, Arjan Buis.

  Quantitative fluorescence imaging of formalin-fixed paraffin-embedded (FFPE) tissue is often limited by intensity heterogeneity, endogenous autofluorescence, and fixation-induced artifacts. Together, these factors reduce analytic accuracy and reproducibility. In murine skeletal muscle, dyes such as Procion Yellow (ProY) are used to identify membrane-compromised cells following injury; however, overlapping autofluorescence and uneven staining hinder reliable quantification. Existing segmentation workflows, including ImageJ-based approaches, are sensitive to these variations, and standard preprocessing methods often fail to adequately normalise fluorescence intensity across whole-slide images. Here, we present a workflow for quantitative analysis of ProY-stained FFPE skeletal muscle. The pipeline combines spectral characterisation of the dye and autofluorescence, optimised whole-slide fluorescence image acquisition, ratiometric intensity normalisation, automated segmentation using Cellpose, adaptive thresholding, and particle analysis. This approach improves segmentation robustness and consistency in highly autofluorescent FFPE tissue sections while reducing user-dependent variability. As proof-of-principle, validation in mechanically injured murine skeletal muscle demonstrated that the workflow could distinguish between different levels of tissue injury. This workflow provides a quantitative approach for fluorescence-based imaging in preclinical studies, with potential for future integration into more standardised clinical histopathology workflows. Although optimised for ProY-labelled skeletal muscle, the pipeline could be adapted to other dyes and tissue types affected by autofluorescence.

Keywords:  FFPE tissue; Fluorescence imaging; Histopathology; Image normalisation; Quantitative image analysis; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ymeth.2026.08.001