bims-cagime 2026-06-21 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–06–21
thirty-two papers selected by
Kıvanç Görgülü, Technical University of Munich

Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.
A single-vesicle fluorescence microscopy platform to quantify phospholipid scrambling.
L1CAM signaling through planar cell polarity drives SOX2 expression and lung adenocarcinoma metastasis.
Targeting the lipid desaturation network in cancer: from metabolic plasticity to precision therapeutics.
A cholesterol-dependent LRRC8A-caveolin-1 axis sustains KRAS/EGFR signaling, ribosome biogenesis and growth in pancreatic ductal adenocarcinoma.
KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.
Stearoyl-CoA desaturase 1 integrates tissue-specific oncogenic pathways into a pan-cancer ferroptosis resistance program.
Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.
Non-selective and selective autophagy as mediators of mechanical forces.
3D multi-omics tumour atlases: from technology to biology and clinical translation.
Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
Extracellular fluid viscosity influences the mechanics and migration of MDA-MB-231 cells in a macromolecule-dependent manner.
Risk of pancreatic cancer associated with precursor lesions in individuals and first-degree relatives: a nationwide cohort study.
Collective lipid dynamics in biomembranes.
Local and global patterns support medical imaging as a biomarker of ageing.
Whole-organ spatial transcriptional analysis at cellular resolution using TRISCO.
Autophagic flux blockade under hypocapnia reveals CO₂-sensitive regulation of autophagy-lysosome homeostasis.
Glycosphingolipids in cell identity: Biosynthesis, functions, and emerging tools.
Targeting the HSPA8-CMA-ATP6V1A Axis Triggers Lysosomal Hyperacidification and Catastrophic Vacuolation in Prostate Cancer.
Adhesion-driven rigidity transition decoupled from density-driven jamming triggers epithelial organization in embryonic tissues.
Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer.
Context dependency in cancer neuroscience.
Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.
Geometric control of motility-induced phase separation.
CD4+ T cells impair tumor growth through IL-3 and TNF-dependent vascular damage.
Stressed lysosome: A theoretical model of lysosomal pH regulation applied to stress conditions.
The heart beats cancer.
Stochastic process description of lipid flip-flop.
Spatial Visual Proteomics: Insights into Tumor Microenvironment Dynamics.
The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
Targeting WFS1 overcomes KRASG12D dependency and adaptive resistance to KRAS inhibition in pancreatic cancer.
Pathways for fast and slow fusion of nanovesicles without membrane rupture.

Nat Commun. 2026 06 15. pii: 5288. [Epub ahead of print]17(1):

Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.

Sofya Tishina, Alina Dahlhaus, Marta Manik, Lejla Mulalic, Janine Murr, Michael Kotliar, Hassan Rakhsh-Khorshid, Myrto Kostopoulou, Florian Hocher, Jenny Stroh, Julia Beck, Riley M Williams, Gülce G Balta, Fanyu Liu, Ali T Abdallah, Christina M Bebber, Moritz Reese, Jonathan K M Lim, Alexander Quaas, Johannes Brägelmann, Manolis Pasparakis, Filippo Beleggia, Siddharth Balachandran, Anna Trauzold, Gianmaria Liccardi, Igor Astsaturov, Maximilian Reichert, Ariadne Androulidaki, Silvia von Karstedt.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death within this decade. Here, we show that its major driver oncogene KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response that primes PDAC cells for necroptosis. Using genetically engineered mouse models, we find that cancer cell-specific deletion of caspase-8 is sufficient to trigger necroptotic cell death, eliminating most pancreatic precursor lesions. Mechanistically, KRAS-driven IFN signalling induces ISGF3-dependent expression of necroptosis-related interferon-stimulated genes, including MLKL. This renders PDAC cells selectively vulnerable to necroptosis upon caspase-8 inhibition. Therapeutically, pharmacologic caspase inhibition reduces tumour burden in aggressive PDAC models and human patient-derived organoids. A pan-cancer transcriptomic analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumour types. These findings reveal a KRAS-induced IFN program that sensitises tumour cells to necroptosis, highlighting a therapeutic vulnerability in PDAC with broader relevance across IFN-activated cancers.

DOI: https://doi.org/10.1038/s41467-026-73189-8
Nat Struct Mol Biol. 2026 Jun;33(6): 1011-1019

A single-vesicle fluorescence microscopy platform to quantify phospholipid scrambling.

Sarina Veit, Grace I Dearden, Kartikeya M Menon, Faria Noor, Indu Menon, Takefumi Morizumi, Oliver P Ernst, Anant K Menon, Thomas Günther Pomorski.

Scramblases are physiologically important proteins that translocate phospholipids bidirectionally across cell membranes. For example, scrambling facilitated by dimers of the voltage-dependent anion channel 1 (VDAC1) enables endoplasmic reticulum-derived phospholipids to cross the outer membrane to enter mitochondria. Here we describe a protocol to obtain lipid translocation rates at a single-protein level, allowing for mechanistic understanding of scramblases. We reconstituted vesicles with fluorescent phospholipids and VDAC1 dimers and use high-throughput imaging to quantify their size and dimer content. We measure scrambling in each vesicle using a new assay and find that individual human VDAC1 dimers scramble lipids at rates ranging from under 100 to over 10,000 per second. This kinetic heterogeneity, masked in ensemble measurements, revealed that rapid scrambling is facilitated by specific VDAC1 dimers. Extending our analyses to bovine opsin, a monomeric G-protein-coupled receptor scramblase, we demonstrate the versatility of our platform for quantifying lipid scrambling and exploring its regulation.

DOI: https://doi.org/10.1038/s41594-026-01821-8
Nat Commun. 2026 Jun 18.

L1CAM signaling through planar cell polarity drives SOX2 expression and lung adenocarcinoma metastasis.

Jin Suk Park, Yasemin Kaygusuz, Carson Kenum, Lan He, Mohamed I Gatie, Xueqian Zhuang, Roshan Sharma, Ronan Chaligné, Umesh K Bhanot, Richard P Koche, Tuomas Tammela, Anna-Katerina Hadjantonakis, Charles M Rudin, Joan Massagué.

Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unclear. Here, we elucidate a process that drives the emergence of SOX2+ metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells at the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions, as well as the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2+ LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.

DOI: https://doi.org/10.1038/s41467-026-74539-2
J Exp Clin Cancer Res. 2026 Jun 17.

Targeting the lipid desaturation network in cancer: from metabolic plasticity to precision therapeutics.

Justyna J Gleba, John A Copland, Han W Tun.

  Lipid desaturation is a fundamental biochemical process essential for maintaining membrane fluidity, energy storage, and cellular signaling. It is increasingly recognized that this homeostatic network is frequently dysregulated by malignant cells to support proliferation, evade programmed cell death, and facilitate immune evasion. There are two primary lipid desaturation pathways: the conversion of saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs) by stearoyl-CoA desaturase 1 (SCD1), and the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) via the fatty acid desaturases (FADS). This review explores how tumors utilize the SCD1 axis to mitigate lipotoxic endoplasmic reticulum (ER) stress and ferroptosis. Furthermore, we discuss how the FADS axis presents a distinct metabolic paradox: while it promotes oncogenic signaling and structural plasticity, it concurrently creates an actionable vulnerability to ferroptosis by enriching membranes with peroxidation-prone PUFAs. This metabolic rewiring provides a strong biological rationale for precision therapeutics.We trace the clinical development of desaturase inhibitors, highlighting the recent entry of SCD1 inhibitor, MTI-301, in a Phase 1 clinical trial for solid tumors and the potential repurposing of Aramchol, while detailing how FADS2 plasticity (the "sapienic shunt") drives therapeutic resistance. By integrating these insights into desaturation lipidomics, metabolic modulation via diet-drug interactions, synergistic combination regimens, and stimuli-responsive nanomedicine, we highlight the translational potential of targeting lipid desaturation to overcome metabolic plasticity and treatment resistance in aggressive malignancies.

Keywords:  Cancer metabolism; ER stress; FADS2; Ferroptosis; Lipid desaturation; MTI-301 (SSI-4); Metabolic plasticity; Precision therapeutics; SCD1; Sapienic shunt

DOI:  https://doi.org/10.1186/s13046-026-03747-x
Oncogene. 2026 Jun 20.

A cholesterol-dependent LRRC8A-caveolin-1 axis sustains KRAS/EGFR signaling, ribosome biogenesis and growth in pancreatic ductal adenocarcinoma.

Qing Ye, Hong-Zhi Liu, Xiao-Qi Wang, Li-Peng Hu, Hui Li, Sheng-Zhe Gong, Yi-Tian Tao, Zheng Wu, Wang-Wang Liu, Feng Han, Lei Zhu, Dong-Xue Li, Xue-Li Zhang, Shu-Heng Jiang, Zhi-Gang Zhang, Yan-Miao Huo, Qi Wo, Qi-Li Peng, Xiao-Mei Yang.

Cellular adaptive volume regulation is essential for maintaining metabolic homeostasis and supporting survival, yet its role in desmoplastic pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. Through comprehensive bioinformatic and functional studies, we identified LRRC8A, the core subunit of volume-regulated anion channels (VRAC), as a central regulator linking volume homeostasis to PDAC progression. Beyond its established role in osmotic stress responses, genetic silencing or pharmacological inhibition of LRRC8A revealed its critical function in proliferation-associated volumetric expansion during S-phase. Functional validation through in vitro proliferation assays, in vivo xenograft models, and patient-derived pancreatic cancer organoids (PDO) demonstrated that LRRC8A critically drives PDAC progression. Mechanistically, LRRC8A coordinates plasma membrane dynamics, cortical cytoskeletal organization, membrane-delimited oncogenic signaling (KRAS/EGFR), and nucleolar ribosome biogenesis to support volumetric expansion during S phase. Co-immunoprecipitation coupled with mass spectrometry identified that LRRC8A forms complexes with Caveolin 1 (CAV1). Disruption of LRRC8A leads to decreased CAV1 protein levels, impaired activation of KRAS and EGFR oncogenic signaling, and suppressed ribosome biogenesis and global protein synthesis. Reciprocally, CAV1 knockdown or cholesterol depletion using lovastatin destabilized LRRC8A in plasma membrane, resulting in reduced cortical F-actin organization, oncogenic signaling and biosynthetic activity, indicating that LRRC8A and CAV1 are mutually stabilized and depend on cholesterol-rich membrane microdomains for proper integration and function. Furthermore, disruption of LRRC8A-CAV1 axis through LRRC8A inhibition or cholesterol depletion potently suppressed PDO growth in vitro. Collectively, our work establishes the LRRC8A-CAV1 complex as a key coordinator of biosynthetic expansion and a promising therapeutic target in pancreatic cancer.

DOI: https://doi.org/10.1038/s41388-026-03864-z
J Lipid Res. 2026 Jun 16. pii: S0022-2275(26)00105-7. [Epub ahead of print] 101079

KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.

Neha Arora, Hong Liang, Walaa Kattan, Wantong Yao, Haoqiang Ying, Junchen Liu, Yong Zhou.

  KRAS mutated at hotspots G12, G13 and Q61 possess profound allele-specific oncogenesis. Signaling of KRAS mutants is mostly compartmentalized to the proteolipid nanoclusters on the plasma membrane (PM), illustrating critical roles of spatiotemporal organization in KRAS cancer signaling. The activated GTP-bound KRAS molecules, including the wild-type and mutants, have been traditionally thought to favor similar lipids. We recently reported distinct lipid sensing capabilities of different KRAS mutants, especially with KRASG12D favoring unsaturated lipids and KRASG12C gaining additional enrichment of saturated lipids. As such, KRAS mutants may respond to lipid acyl chain remodeling in an allele-specific manner. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) facilitates the incorporation of saturated fatty acid chains to phospholipids. Here, we found that cells stably expressing LPCAT1 contain higher levels of saturated lipids and lower levels of unsaturated PS species. Electron microscopy (EM)-spatial analysis revealed that LPCAT1 expression disrupts the nanoclustering of KRASG12D on the PM, without affecting that of KRASG12C and HRASG12V. Elevation of LPCAT1 expression suppresses signaling, proliferation and colony formation of KRASG12D-expressing human pancreatic cancer cells, while promoting those of KRASG12C-expressing cells. Knocking out LPCAT1 depletes saturated lipids and reduces colony formation of KRASG12C cells. We further found that changing LPCAT1 expression specifically targets KRAS mutant-expressing cells, without affecting cells expressing wild-type KRAS. Mouse embryonic fibroblasts transformed with KRASG12C also contain more saturated lipids than KRASG12D MEFs. Thus, activities of KRAS mutants depends on lipid acyl chain remodeling in an allele-specific manner.

Keywords:  KRAS; Lysophosphatidylcholine acyltransferase 1; acyl chains,electron microscopy; cancer biology; nanoclustering; phosphatidylserine; phospholipids

DOI:  https://doi.org/10.1016/j.jlr.2026.101079
Cell Death Dis. 2026 Jun 19.

Stearoyl-CoA desaturase 1 integrates tissue-specific oncogenic pathways into a pan-cancer ferroptosis resistance program.

Francesca Ascenzi, Giovanni Blandino, Gennaro Ciliberto, Rita Mancini.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a promising therapeutic vulnerability in cancer. Among its key modulators, stearoyl-CoA desaturase 1 (SCD1) plays a pivotal role in ferroptosis resistance by converting saturated fatty acids into monounsaturated fatty acids (MUFAs), thereby limiting the accumulation of highly peroxidizable polyunsaturated fatty acids (PUFAs) and stabilizing membrane integrity under oxidative stress. Multiple oncogenic, transcriptional, epigenetic, and microenvironmental cues enhance tumor survival by promoting SCD1-dependent ferroptosis resistance. Despite this diversity of regulatory inputs, a unifying principle emerges across tumor types: SCD1 activity preserves lipid desaturation as a dominant metabolic strategy to suppress ferroptotic cell death. In this review, we critically analyze how SCD1-dependent ferroptosis resistance is shaped by tumor-specific metabolic states, microenvironmental pressures, and regulatory hierarchies across multiple malignancies. We identify recurring mechanistic themes through which SCD1 integrates redox control, lipid metabolism, stemness, and therapy resistance, while highlighting how these processes are differentially regulated across tissues. Preclinical evidence indicates that targeting SCD1, particularly in rational combination with ferroptosis inducers, chemotherapy, radiotherapy, or immunotherapy, can lower the ferroptotic threshold and overcomes treatment resistance. Finally, we discuss translational challenges and emerging strategies, including tumor-selective delivery, adaptive dosing, and context-specific combinations, that may enable safe and effective exploitation of the SCD1-ferroptosis axis in cancer therapy.

DOI: https://doi.org/10.1038/s41419-026-08982-w
Nat Cell Biol. 2026 Jun 19.

Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.

Steven T Nguyen, Richard L Watson, Fangyuan Gao, Melissa Campos, Sunhee Jung, Laurence J Seabrook, Maxwell C Kim, Eric A Hanse, Ying Yang, Mei Kong, Jonathan E Zuckerman, Renata C Pereira, Isidro B Salusky, Sergio D Catz, Cholsoon Jang, Dorota Skowronska-Krawczyk, Lauren V Albrecht.

Lysosomes are integral organelles that communicate cellular status to an entire tissue through mechanisms that are poorly defined. Here we developed an unbiased platform, integrating human plasma metabolomes and single-lysosome metabolomics, and show the byproducts of proteolysis are an unexpected class of signalling molecules. We show that dimethylarginine is a lysosomal-derived metabolite and a predictor of patient morbidity. Genetic depletion of a lysosomal exporter, cystinosin, accumulated dimethylarginine in lysosomes. Leveraging a lysosomal storage disease with cystinosin mutations, we show that the rapid plasticity of dimethylarginine compartmentalization ensures cell and tissue homeostasis. Strikingly, lysosomal entrapment of dimethylarginine in patients and disease models corresponds with lipid accumulation, lipid droplets and lipotoxicity. Exogenously restoring asymmetric dimethylarginine buffers oxidative stress, decreasing lipid peroxidation and cell death. These data show that dimethylarginine engages an interorganellar process-with peroxisomes, lysosomes and lipid droplets-that confers a crucial adaptive response mechanism.

DOI: https://doi.org/10.1038/s41556-026-01970-4
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00155-8. [Epub ahead of print]404 233-258

Non-selective and selective autophagy as mediators of mechanical forces.

Maraiza Alves Teixeira, Nicolas Dupont.

  Autophagy is a fundamental cell biological process that controls the quality and quantity of the eukaryotic cytoplasm. Dysfunctional autophagy, when defective or excessive, has been linked to human pathologies. Autophagy can randomly degrade cytoplasmic components in a non-selective manner commonly referred to as bulk autophagy. In contrast, selective forms of autophagy specifically target cytoplasmic structures such as organelles thereby being important for cellular quality control and organelle homeostasis. Recent studies demonstrate the role of bulk and selective autophagy in the integration of physical constraints. Mechanical forces, combine with biochemical signals control the development and the physiological functions of different organs and can also contribute to the progression of various diseases. The aim of this Review is to summarize and discuss our current knowledge on the role of autophagy in regulating a broad range of cellular responses, from morphology, metabolism, to inflammation and senescence, in the context of mechanical forces. Additionally, where relevant, we will also discuss the potential implications of mechanical stress-induced autophagy in pathologies.

Keywords:  Bulk autophagy; Compression; ECM stiffness; Selective autophagy; Shear Stress; Stretching; Tension

DOI:  https://doi.org/10.1016/bs.ircmb.2025.10.007
Nat Rev Cancer. 2026 Jun 15.

3D multi-omics tumour atlases: from technology to biology and clinical translation.

Miao Liu, Jorge Villazon, André Forjaz, Xiaolong Tian, Rong Fan, Siyuan Wang, Lingyan Shi, Denis Wirtz, Ashley L Kiemen.

Human tumours consist of highly heterogeneous and interacting cell types organized within a complex 3D space, forming a dynamic ecosystem that evolves through the development of pre-malignant lesions, tumour initiation, progression, invasion and metastasis. Understanding the operational principles of tumour evolution at a holistic 3D level is critical for improving the ability to intercept and treat cancer early. Emerging technologies in spatial multi-omics and the generation of 3D tumour atlases are beginning to address this critical need. These efforts aim to capture the intricate interactions within precancerous lesions, tumours and their surrounding ecosystems over space and time. In this Review, we highlight emerging tools developed within and beyond the tumour atlas community and explore their potential in constructing comprehensive 3D tumour atlases. Such atlases have the potential to reveal novel biomarkers for risk stratification, early detection, preventive intervention, and transformative diagnostic and treatment strategies. Furthermore, a 3D tumour atlas can generate new insights into the molecular and cellular mechanisms driving human tumour evolution, paving the way for future research and innovation in cancer biology.

DOI: https://doi.org/10.1038/s41568-026-00940-0
Nat Cell Biol. 2026 Jun 15.

Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.

Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.

Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.

DOI: https://doi.org/10.1038/s41556-026-01991-z
FEBS J. 2026 Jun 15.

Extracellular fluid viscosity influences the mechanics and migration of MDA-MB-231 cells in a macromolecule-dependent manner.

Ian M Smith, Nikka Givpoor, Chenchen Handler, Ariel Abraham, Shohini Banerjee, Giuliano Scarcelli, Kimberly M Stroka.

  Cells constantly experience the ubiquitous mechanical cue of extracellular fluid (ECF) viscosity, which dictates essential cell functions across physiological and pathophysiological conditions. Recent studies have linked increased ECF viscosity to the enhanced migratory capacity of cells across a wide range of environments. The mechanical properties of cells have been shown to regulate cell motility. As ECF viscosity is mechanical, the resulting increased cell migration due to ECF viscosity could be mediated by modulated cellular mechanoresponses. In this work, we varied extracellular fluid viscosity through addition of methylcellulose (MC) or polyvinylpyrrolidone (PVP) to the cell culture media. Cell morphology and migration parameters were quantified from phase-contrast microscopy images and were measured as a function of extracellular fluid viscosity and/or osmotic shocks. We also utilized a microfluidic cell deformation device and Brillouin microscopy to measure the mechanical properties of cells as a function of extracellular fluid viscosity. We demonstrated that increased ECF viscosity leads to changes in cell mechanical properties and invasive potential in a macromolecule-dependent manner.

Keywords:  cell deformability; cell mechanics; cytoskeleton; extracellular fluid; mechanotyping

DOI:  https://doi.org/10.1111/febs.70623
Clin Gastroenterol Hepatol. 2026 Jun 15. pii: S1542-3565(26)00443-X. [Epub ahead of print]

Risk of pancreatic cancer associated with precursor lesions in individuals and first-degree relatives: a nationwide cohort study.

Jonas F Ludvigsson, Jiangwei Sun, Chen Yuan, Miroslav Vujasinovic, Johannes-Matthias Löhr, Brian M Wolpin, Qiao-Li Wang.

   BACKGROUND AND AIMS: To evaluate risk of pancreatic cancer in individuals with pathologically confirmed precursor lesions including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), and mucinous cystic neoplasia (MCN), and their first-degree relatives (FDRs).
METHODS: Using nationwide population-based cohort study, we included all histopathologically diagnosed pancreatic precursors during 1981-2017 and up to 5 matched general population references in Sweden, and their FDRs. Participants were followed through January 1st, 2020. Incidence rates and 95% confidence intervals (CIs) were computed with Poisson model and hazard ratios (HRs) were calculated using Cox proportional hazards regression.
RESULTS: We identified 3,980 index participants (681 precursor patients and 3,299 reference individuals) and 25,986 FDRs. Twenty-four index participants and 136 FDRs developed pancreatic cancer during follow-up. Compared with reference individuals, precursor patients had a 7.25-fold (95% CI 2.13-24.71) higher risk of pancreatic cancer, corresponding to 330 per 100,000 person-years (95% CI 191-568) in precursors vs 40 per 100,000 person-years (95% CI 22-71) in reference individuals, with a particularly high incidence of pancreatic cancer in PanIN participants (785 per 100,000 person-years; 95% CI 446-1,382). Compared with FDRs of reference individuals, FDRs of precursor patients had an HR of 2.59 (95% CI 1.71-3.91) for pancreatic cancer, and HR of 15.94 (95% CI 3.04-83.69) for early-onset pancreatic cancer (aged <50 years). Pancreatic cancer risks in FDRs were similar across precursor subtypes in index participants.
CONCLUSIONS: A substantially higher risk of pancreatic cancer in pathologically confirmed precursor patients and their FDRs were observed. A family history of these lesions may be important in individual risk assessment of pancreatic cancer.

Keywords:  familial risk; pancreatic ductal adenocarcinoma; precursor lesion; young-onset pancreatic cancer

DOI:  https://doi.org/10.1016/j.cgh.2026.06.009
Biochim Biophys Acta Biomembr. 2026 Jun 18. pii: S0005-2736(26)00056-8. [Epub ahead of print] 184553

Collective lipid dynamics in biomembranes.

Michael F Brown.

  Cellular lipids are wonders of biomolecular self-organization whose structure and dynamics are intimately connected with their functionality. Here we review the development and use of NMR spectroscopy in the study of lipid membranes. For liquid-crystalline bilayers, the structure is described by orientational order parameters, while the dynamics entail fluctuations about the mean geometry. Addressing the information gap between molecular structure, dynamics, and function involves magnetic resonance spectroscopy combined with X-ray and neutron scattering approaches. Cholesterol gives a crucial test in liquid-ordered (lo) membranes, where the bending rigidity oppositely affects solid-state NMR observables-the order parameters increase yet the relaxation rates decrease. By contrast, nonionic surfactants in the liquid-disordered (ld) state soften the bilayer and decrease the order parameters, thereby enhancing the spin relaxation. This enigma is explained by a model-free power-law that combines the mean-squared amplitudes and fluctuation rates. Collective modes appear on the mesoscale of the bilayer thickness and less, indicating how membrane elasticity emerges from atomistic-level interactions that drive the response to external forces. The unified power-law scaling shows how the bilayer fluidity corresponds to a hydrocarbon liquid of similar chain length. Magnetic resonance spectroscopy thus yields insights into properties that underlie bilayer phase transitions, curvature, and protein-lipid interactions.

Keywords:  Bending elasticity; Cholesterol; Curvature; Fluidity; Lipidomics; Molecular dynamics; X-ray & neutron scattering

DOI:  https://doi.org/10.1016/j.bbamem.2026.184553
Commun Med (Lond). 2026 Jun 13. pii: 335. [Epub ahead of print]6(1):

Local and global patterns support medical imaging as a biomarker of ageing.

Tamara T Mueller, Sophie Starck, Rozafë Llalloshi, Georgios Kaissis, Alexander Ziller, Robert Graf, Christopher Schlett, Steffen Ringhof, Fabian Bamberg, Mark Wielpütz, Henry Völzke, Michael Leitzmann, Thoralf Niendorf, Thomas Keil, Lilian Krist, Tobias Pischon, André Karch, Klaus Berger, Jan Kirschke, Daniel Rueckert, Rickmer Braren.

BACKGROUND: Understanding human ageing across multiple organs is essential for characterising individual health trajectories and identifying abnormal ageing processes. Multi-organ imaging provides an opportunity to quantify biological ageing beyond chronological age. The aim of this study is to assess organ-specific and whole-body ageing patterns and their associations with disease and lifestyle factors.
METHODS: In this large-scale study, we evaluate biological ageing patterns using 70,000 MRI scans from the UK Biobank and the German National Cohort. We employ 3D ResNet-18 models to predict chronological age from various body regions (brain, heart, liver, spine, lungs, muscle, and intestine) and the whole body. From these predictions, we derive "age gaps" relative to a strictly healthy reference cohort, which enables the identification of accelerated ageing patterns. We then evaluate associations with chronic diseases and lifestyle factors, and a virtual ageing framework was developed to explore counterfactual scenarios by substituting anatomical regions across subjects, quantifying local impacts on global biological age.
RESULTS: Here we show significant associations between detected accelerated ageing and specific chronic diseases, including multiple sclerosis and chronic obstructive pulmonary disease, as well as lifestyle factors such as smoking and physical activity. Virtual substitution of anatomical regions demonstrates that local substitutions can influence global ageing patterns.
CONCLUSIONS: This study demonstrates that multi-organ imaging enables the detection of abnormal ageing patterns at both local and global levels. The presented framework provides a foundation for improved risk stratification and supports the development of personalised approaches to health assessment and disease prevention.

DOI: https://doi.org/10.1038/s43856-026-01722-3
Nat Protoc. 2026 Jun 17.

Whole-organ spatial transcriptional analysis at cellular resolution using TRISCO.

Yue Li, Abigail Walton, Judith C Kreutzmann, Lea Lydolph Larsen, Ilse Eidhof, Jacob Lercke Skytte, Casper Gravesen Salinas, Urmas Roostalu, Jacob Hecksher-Sørensen, Shigeaki Kanatani, Per Uhlén.

The emerging field of 3D histology centers on the molecular profiling of intact organs for a comprehensive understanding of biological systems. While current methods focus largely on protein visualization, techniques for whole-organ RNA transcript imaging remain underdeveloped. Here we present a detailed protocol for Tris buffer-mediated retention of in situ hybridization chain reaction signal in cleared organs (TRISCO), a method for single-cell RNA three-dimensional mapping across tissue volumes. By ensuring homogeneous and well-preserved labeling throughout the entire tissue, TRISCO has been successfully applied to several mouse organs, including the brain, lung, heart, kidney and spinal cord, as well as to rat and guinea pig brains. The protocol is straightforward, is adaptable to diverse laboratory setups and research questions and avoids complex instrumentation, specialized expertise or harsh chemical treatments that might limit its applicability. The workflow, which can be completed in 10-15 days, includes flexible stopping points for convenient scheduling and is suitable for users with expertise in light-sheet microscopy and animal handling.

DOI: https://doi.org/10.1038/s41596-026-01386-2
Biol Open. 2026 Jun 16. pii: bio.062414. [Epub ahead of print]

Autophagic flux blockade under hypocapnia reveals CO₂-sensitive regulation of autophagy-lysosome homeostasis.

Naghmana Ashraf, Zhen Sun, Jeanine L Van Nostrand.

  Hypocapnia, a reduction in partial pressure of carbon dioxide (CO₂), commonly occurs in clinical contexts such as mechanical ventilation, panic disorder, and brain injury, yet its impact on cellular homeostasis remains poorly understood. Given the central role of autophagy in stress adaptation, we investigated how low CO₂ influences autophagic flux and lysosomal function. We found that hypocapnia induces autophagosome accumulation while impairing cargo degradation, indicating a blockade in autophagic flux. This response was accompanied by increased lysosome biogenesis but, paradoxically, reduced autophagosome-lysosome fusion and lysosomal proteolytic activity. Mechanistically, hypocapnia promoted TFE3 dephosphorylation and nuclear translocation, driving transcriptional activation of lysosomal genes. Concurrently, suppressed AMPK activity and sustained mTOR signaling revealed a unique metabolic state that uncouples energy stress from canonical autophagy control. As such, inhibition of both mTORC1 and mTORC2 was sufficient to restore autophagic flux. Notably, increased pH was not sufficient to drive this program. These findings identify hypocapnia as a previously unrecognized modulator of autophagy that disrupts autophagosome-lysosome fusion and terminal degradation, positioning CO₂ tension as a critical regulator of cellular stress responses.

Keywords:  Autophagy; Carbon Dioxide; Hypocapnia; Lysosome; TFE3; mTOR

DOI:  https://doi.org/10.1242/bio.062414
Trends Biochem Sci. 2026 Jun 18. pii: S0968-0004(26)00171-4. [Epub ahead of print]

Glycosphingolipids in cell identity: Biosynthesis, functions, and emerging tools.

Pavel Barahtjan, Nika Goršek, Jean Andrea Maillat, Giovanni D'Angelo.

  Cell fate is shaped by external cues and intrinsic cellular states. While supracellular signals, such as growth factors, provide instructive guidance, emerging evidence highlights the role of cell-autonomous properties in modulating these responses. Among these, lipid membrane composition, especially glycosphingolipids (GSLs), has gained attention as a contributor to cellular identity. GSL biophysical properties guide the formation of membrane nanodomains, which serve as platforms for receptor signaling and protein sorting, while their structural heterogeneity enables distinct interactions with signaling molecules and recognition factors. In this review, we discuss the biosynthesis and organization of GSLs, their biological roles, and emerging technologies for their analysis. Together, these studies support the view that GSLs contribute to cell-type-specific membrane properties and help shape cellular states and identity.

Keywords:  MALDI-MSI; bifunctional glycosphingolipids; cell identity; chemical biology; glycosphingolipid biosynthesis; glycosphingolipids

DOI:  https://doi.org/10.1016/j.tibs.2026.05.009
Adv Sci (Weinh). 2026 Jun 19. e76165

Targeting the HSPA8-CMA-ATP6V1A Axis Triggers Lysosomal Hyperacidification and Catastrophic Vacuolation in Prostate Cancer.

Bingzheng An, Ze Gao, Shuo Chen, Liwei Meng, Chen Zhang, Kefan Song, Haochen Cui, Lei Yan, Zhiqing Fang.

  Prostate cancer (PCa) ranks among the most common and deadly malignancies worldwide. The clinical treatment of advanced prostate cancer is particularly challenging due to acquired drug resistance. Autophagy and lysosome-related pathways are key drivers of this resistance. Targeting the lysosome represents a potential therapeutic strategy for PCa. In this study, we identified Heat Shock Protein Family A Member 8 (HSPA8) as a critical functional node of Aloperine (ALO). ALO suppresses autophagic flux, disrupts lysosomal homeostasis, and induces lysosomal vacuolation in cancer cells by inhibiting the function of HSPA8, impairing chaperone-mediated autophagy (CMA)-mediated ATP6V1A degradation. The resulting pathological accumulation and enhanced V1-V0 association of the V-ATPase complex drive pronounced lysosomal hyperacidification and severe osmotic swelling. This biochemical and physical stress is associated with lysosomal membrane permeabilization (LMP) and downstream loss of lysosomal integrity. Furthermore, we reveal that ALO-induced vacuolation triggers a compensatory upregulation of cholesterol biosynthesis to buffer membrane expansion; preemptively disrupting this adaptive response with the DHCR7 inhibitor AY9944 yields significant synergistic lethality. Collectively, our findings reveal the specific cytotoxic mechanism of ALO and demonstrate that pharmacological targeting of the HSPA8-CMA-ATP6V1A axis is a valuable strategy for inducing lethal lysosomal vacuolation in advanced PCa.

Keywords:  HSPA8; V‐ATPase; chaperone‐mediated autophagy; lysosomal membrane permeabilization; osmotic stress

DOI:  https://doi.org/10.1002/advs.76165
Nat Phys. 2026 ;22(6): 941-953

Adhesion-driven rigidity transition decoupled from density-driven jamming triggers epithelial organization in embryonic tissues.

Laura Rustarazo-Calvo, Cristina Pallares-Cartes, Adrián Aguirre-Tamaral, Elisa Floris, Maximilian Hingerl, Camilla Autorino, Arif Ul Maula Khan, Bernat Corominas-Murtra, Nicoletta I Petridou.

  The active regulation of tissue material properties via phase transitions is central in morphogenesis. Transitions occur abruptly at critical points in different control parameters, such as cell density, shape or adhesion. Whether these parameters are interdependent, and perform redundant or distinct functions, is unknown. Here we show that depending on the co-regulation of multiple control parameters, a tissue not only tunes its deformability but also its morphogenetic trajectory. We theoretically define a phase diagram capturing the material states of zebrafish pluripotent tissues undergoing epiboly-a tissue movement occurring during gastrulation-and show that they simultaneously cross critical points in cell density, connectivity and adhesion strength. We then combine optogenetics, biophysical measurements and quantitative morphometrics to independently modulate each parameter in vivo, and identify adhesion as the main determinant of tissue rheology. Further decoupling adhesion from density and inducing adhesion-driven rigidification in unjammed pluripotent tissues is sufficient to switch their morphogenetic program and trigger epithelial organization. This switch in tissue reorganization is achieved via tricellular junction formation, followed by lumenogenesis and the initiation of apical polarity. Our work reveals that the nonlinear dynamics of emergent tissue mechanics are mechanisms of tissue organization and morphogenesis.

Keywords:  Biological physics; Biophysics; Phase transitions and critical phenomena; Soft materials; Statistical physics

DOI:  https://doi.org/10.1038/s41567-026-03276-6
Nat Commun. 2026 Jun 19.

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer.

Chaitanya N Parikh, Kelly D DeMarco, Nikita Bhalerao, Hadiya K Giwa, Griffin I Kane, Ronnie W Dinnell, Boyang Ma, Haruka Mori, Meghan L Brassil, Katherine C Murphy, Zhen Zhao, Calvin Johnson, Shriram Ramani, Lin Zhou, Loretah Chibaya, Youwei Qiao, Kai Hu, Lihua Julie Zhu, Brian C Lewis, Wen Xue, Jason R Pitarresi, Prabhani U Atukorale, Marcus Ruscetti.

Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses. Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC. Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8+ T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models. Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8+ T cell priming locally and systemically that prolongs animal survival after a single dose. Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence. These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC.

DOI: https://doi.org/10.1038/s41467-026-74574-z
Cancer Cell. 2026 Jun 18. pii: S1535-6108(26)00261-8. [Epub ahead of print]

Context dependency in cancer neuroscience.

Alexander Birbrair, David J Simon, Sebastien Talbot, Shengtao Zhou.

Neural signaling shapes tumor progression, but it is not intrinsically tumor-promoting or tumor-restrictive. We argue that neural directionality is context-dependent and governed by tumor kinetics, tissue architecture, neural state, receptor and target-cell topology, immune-host biology, and treatment history. We propose a mechanistically interpretable and clinically actionable reporting framework for precision neuromodulatory oncology.

DOI: https://doi.org/10.1016/j.ccell.2026.05.016
Cell Death Dis. 2026 Jun 17.

Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.

Sara Verdura, Àngela Llop-Hernández, Travis Van der Steen, José Antonio Encinar, Begoña Martin-Castillo, Elisabet Cuyàs, Ruth Lupu, Javier A Menendez.

Therapy-induced senescence (TIS) in cancer cells can be triggered by radiotherapy, chemotherapy, and certain targeted therapeutics. Here, we demonstrate that a new form of TIS, termed fatty acid synthesis therapy-induced senescence (FASTIS), can be induced by pharmacologically targeting de novo lipogenesis. Cancer cells can evade the anti-proliferative effects of clinically relevant inhibitors of core lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), by entering in a senescence-like state. FASTIS cancer cells acquire the classical senescence hallmarks, such as cytomorphological remodeling, increased senescence-associated beta-galatosidase (SA-β-gal) activity, activation of cell cycle arrest markers, and hypersensitivity to IFNγ-induced activation of the immune checkpoint PD-L1. mRNA sequencing reveals an FASTIS-associated transcriptomic profile that overlaps between ACC and FASN inhibitors yet differs significantly from that of other mechanistically diverse TIS inducers, including bleomycin, alisertib, doxorubicin, and palbociclib. The FASTIS-encoding transcriptome is characterized by the activation of cholesterol- and acetyl-CoA-related lipogenic pathways, as well as cell-intrinsic innate immune responses. This profile is characterized as highly senescent (≥0.95) by the machine learning-based senescence predictor SENCAN. Mapping the metabolome and lipidome in FASTIS cells reveals a significant sterol lipid enrichment, including substantial increases in intracellular cholesterol levels. Pharmacological blockade of cholesterol synthesis or promotion of lysosomal cholesterol accumulation, prevents or potentiates the occurrence of SA-β-gal+ FASTIS cells, respectively. Cytokine arrays and miR-146a reporter-based screens revealed that the FASTIS-associated secretory phenotype (FASASP) is highly enriched in immunomodulatory factors but not in inflammatory components. FASTIS cancer cells exhibit an increased overall level of mitochondrial priming, making them highly susceptible to targeted senolysis by BCL-xL-targeting BH3 mimetics and cytokine-activated T cells. The FASTIS phenomenon is a therapeutic outcome through which cancer cells adapt to survive clinical-grade lipogenesis inhibitors. The cholesterol-addicted FASTIS fate can be rationally exploited as a collateral sensitivity in "one-two punch" senogenic-(immuno)senolytic strategies.

DOI: https://doi.org/10.1038/s41419-026-08992-8
Soft Matter. 2026 Jun 17. 22(23): 4082-4092

Geometric control of motility-induced phase separation.

Toler H Webb, Helen S Ansell, Daniel M Sussman.

Curvature fundamentally alters the collective properties of soft, active, and biological materials. Here we study motility-induced phase separation (MIPS), a canonical non-equilibrium transition, and demonstrate that even weak and slowly varying curvature provides robust geometric control over the dense MIPS phase. This includes dictating both the location and morphology of the MIPS cluster, even in regimes where curvature has minimal effect on the overall phase boundaries. Focusing on active Brownian particles confined to the surface of a torus, we show that varying the aspect ratio drives a structural transition of the dense cluster from a disk localized at the outer equator to a band wrapping the minor circumference. We then discuss how the curved geometry provides a platform for comparing different theoretical frameworks for the MIPS phase: by analyzing the geometries of the cluster boundaries, we show that the dense phase shape is more consistent with a boundary-length-minimizing, thermodynamic picture than with the simplest kinetic picture in the large-particle-number limit. Our results establish curved space not only as a tool to shape and guide non-equilibrium dynamics, but as a uniquely sensitive arena for probing the fundamental mechanisms of active matter.

DOI: https://doi.org/10.1039/d6sm00213g
Science. 2026 Jun 18. 392(6804): eads7910

CD4+ T cells impair tumor growth through IL-3 and TNF-dependent vascular damage.

Qiaoshi Lian, Jia Nie, Jatinder Singh, Qiang Chen, Jennifer Matta, Waipan Chan, Mariah Balmaceno-Criss, Melanie S Vacchio, Weiming Yu, Alexander D Clark, Elijah Edmondson, Michael C Kelly, Ronald N Germain, Rémy Bosselut.

Most cancer immunotherapy strategies are focused on direct tumor killing by immune cells, especially T lymphocytes. Clinical and conceptual limitations of these approaches create a need for additional strategies. We identified a tumor stroma-targeting mechanism in which tumor antigen-specific CD4+ T cells inhibit tumor growth through myeloid cell and tumor necrosis factor (TNF)-dependent vascular damage. Multiplex immunofluorescence and single-cell and tissue transcriptomics showed that CD4+ T cells trigger the formation of perivascular myeloid cell clusters containing "classically activated" macrophages that produce TNF in response to T cell-derived interleukin-3. TNF causes intratumoral endothelial damage and blood supply disruption, which are associated with localized tumor cell death. Thus, intratumoral antigen-triggered T cell activation can mediate antitumor effects without direct recognition of living tumor cells, thereby avoiding many of the inhibitory mechanisms that limit anti-tumor immunity.

DOI: https://doi.org/10.1126/science.ads7910
J Gen Physiol. 2026 Jul 06. pii: e202413745. [Epub ahead of print]158(4):

Stressed lysosome: A theoretical model of lysosomal pH regulation applied to stress conditions.

Sofia F Nazarova, Vadim A Alekhin, Vladislav V Pavlov, Yury S Semenov, Siarhei M Bukhalovich, Fedor M Tsybrov, Andrey O Bogorodskiy, Diana F Bagaeva, Olga V Moiseeva, Anastasiia D Vlasova, Anatolii E Mikhailov, Yayu Wang, Andrey V Rogachev, Semen V Nesterov, Valentin I Borshchevskiy, Chunlei Cang, Piotr D Bregestovski, Valentin I Gordeliy, Nikolay S Ilyinsky.

Lysosomes are essential organelles in eukaryotic cells, required for autophagy, endocytosis, pathogen defense, cell signaling, and metabolic homeostasis. A model of lysosomal ion and water fluxes that captures the synchronized, interdependent operation of ion transporters and diffusion enables prediction of organellar responses to external perturbations and supports the design and interpretation of experiments. Particularly with the advent of organelle-targeted rhodopsin-based optogenetics, there is a pressing need to predict cellular outcomes following light-driven, specific ion transport in lysosomes and other organelles. Currently, no models of lysosomal ion balance fully align with existing experimental data or enable simulation of the organelle's response to stress. Here, we present an updated interactive model that recapitulates appropriate stress responses. We incorporated the functional activities of TPC1 and TMEM165, in addition to the previously included vATPase, ClC-7, TRPML1, and passive ion and water fluxes. The model remains robust during lysosomal maturation, membrane permeabilization, swelling, deacidification induced by vATPase inhibition or additional optogenetics-like proton efflux, and accumulation of weakly basic cationic amphiphilic drugs. Our simulations indicate that lysosomal Ca2+ depletion couples with organellar deacidification triggered by either increased proton leakage or vATPase inhibition, with potential involvement of TMEM165 weakening. Beyond predicting stress-response dynamics, the model enables investigation of highly selective perturbations that can be experimentally induced using optogenetics. Elucidating the mechanisms underlying stable, stress-resilient lysosomal function offers insights for developing anti-disease and antiaging interventions. Further model refinement critically depends on experimental characterization of the lysosomal NHE-like protein mediating sodium influx.

DOI: https://doi.org/10.1085/jgp.202413745
Trends Cancer. 2026 Jun 19. pii: S2405-8033(26)00132-9. [Epub ahead of print]

The heart beats cancer.

Jacky G Goetz.

  Heart cancer or metastasis is very rare, yet the heart is highly vascularized and mechanically pumps blood flow through our body. Recent findings from Ciucci et al. show that mechanical load in the beating heart suppresses cancer growth via Nesprin-2-dependent mechanotransduction, which changes histone methylation and chromatin compaction to keep proliferation genes less active in cardiac tumor cells.

Keywords:  cancer; heart; mechanical loading

DOI:  https://doi.org/10.1016/j.trecan.2026.06.004
J Chem Phys. 2026 Jun 21. pii: 234903. [Epub ahead of print]164(23):

Stochastic process description of lipid flip-flop.

Nathaniel Wesnak, Markus Deserno.

Since lipid bilayers are self-assembled macroscopic aggregates, their constituent lipid molecules can spontaneously transition between the two leaflets. This so-called "flip-flop" is almost universally described via first-order chemical kinetics: the net "flux" leaving a given leaflet is proportional to the number of lipids it contains. However, this model ignores interactions, such as those arising from packing or non-ideal mixing, and restricting the analysis to macroscopic rate equations misses fluctuations. Here, we employ tools from the field of stochastic processes to examine the impact of stress and non-ideal mixing on lipid flip-flop, and we discuss several methods for quantifying the associated fluctuations-ranging from stochastic trajectories to evolution equations for probability densities. We show that differential stress strongly enhances the rate at which lipid abundance asymmetry decays, while compositional relaxation in mixed systems can be closer to ideal under suitable conditions. For the case of binary systems in the presence of packing constraints, we employ a linear noise approximation to the system's master equation and show that it leads to an easily manageable Ornstein-Uhlenbeck process for the fluctuations of (and correlations between) compositions. We also show how to include non-ideal mixing, which leads to large and very slow compositional fluctuations as we approach the critical point.

DOI: https://doi.org/10.1063/5.0326588
Genomics Proteomics Bioinformatics. 2026 Jun 16. pii: qzag045. [Epub ahead of print]

Spatial Visual Proteomics: Insights into Tumor Microenvironment Dynamics.

Peiwu Huang, Changying Fu, Qian Kong, Ruijun Tian.

  The tumor microenvironment, a dynamic network of cancer, immune, stromal, and extracellular matrix components, dictates tumor progression and therapeutic resistance. Traditional proteomics, while informative, homogenizes tissues, obscuring the spatial context critical for deciphering tumor heterogeneity and cellular crosstalk. This review explores advancements in spatial visual proteomic technologies that preserve spatial architecture to decode tumor microenvironment complexity. Key methodologies encompass laser capture microdissection for precise cell segmentation, advanced antibody-based platforms for multiplexed proteomic profiling, and emerging innovations such as tissue expansion microscopy for enhanced resolution, and chemical biology-based probes for cell-type-specific proteome profiling. Innovations in sample preparation, such as microfluidic systems and automated workflows, enhance sensitivity and scalability, enabling single-cell resolution. Computational tools address challenges in cell segmentation, data deconvolution, and multi-omics integration, bridging proteomic, genomic, and transcriptomic datasets. Applications highlight tumor heterogeneity, stromal-immune interactions, and spatially resolved metabolic reprogramming, offering insights into immune evasion and therapeutic resistance. We underscore the transformative potential of spatial proteomics in precision oncology, enabling biomarker discovery, prognostic stratification, and tailored therapies. Future directions emphasize enhancing multimodal integration, refining AI-driven tools, and translating findings into clinical practice.

Keywords:  Multi-omics integration; Multiplexed imaging; Precision medicine; Spatial proteomics; Tumor microenvironment

DOI:  https://doi.org/10.1093/gpbjnl/qzag045
Cell Metab. 2026 Jun 15. pii: S1550-4131(26)00193-2. [Epub ahead of print]

The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.

Luigi Ferrucci, Stefano Donega, Allison B Herman, Rafael de Cabo, Myriam Gorospe.

  Aging tissues experience a gradual decline in perfusion and metabolic resilience due to complex interactions among extracellular matrix (ECM) remodeling, vascular dysfunction, and mitochondrial impairment. Stiffening of the ECM that results from collagen crosslinking, elastin loss, and basement membrane thickening reduces vascular compliance and impairs local angiogenesis. The consequent reduction in capillaries and diminished endothelial reactivity leads to ongoing or intermittent hypoxia, which triggers changes in transcriptomic and proteomic programs that inhibit oxidative phosphorylation and facilitate the production of reactive oxygen species. Under these conditions, mitochondria produce less ATP than is needed for homeostatic repair. This energetic breakdown triggers cellular senescence and inflammation, further increasing ECM stiffening, and thus creating a self-sustaining feedback loop that accelerates tissue aging and functional decline. Such a continuum from ECM stiffening to mitochondrial dysfunction may be considered a new therapeutic target for strategies aimed at maintaining vascular integrity, mitochondrial health, and cellular homeostasis during aging.

Keywords:  extracellular matrix; hypoperfusion; mitochondrial dysfunction; senescence

DOI:  https://doi.org/10.1016/j.cmet.2026.05.008
NPJ Precis Oncol. 2026 Jun 15. pii: 241. [Epub ahead of print]10(1):

Targeting WFS1 overcomes KRASG12D dependency and adaptive resistance to KRAS inhibition in pancreatic cancer.

Yixi Chen, Jingwen Zhang, Ying Miao, Jiayu Wang, Jingtong Na, Xiyu Liu, Zhengfang Yi, Huang Chen, Mingyao Liu.

KRASG12D-driven pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge characterized by limited treatment options. While MRTX1133, a potent and selective KRASG12D inhibitor, is currently under clinical evaluation, the emergence of acquired resistance restricts its long-term therapeutic efficacy. In this study, we identified Wolfram syndrome 1 (WFS1) as a potential molecular vulnerability in KRASG12D-driven PDAC. Our findings suggest that WFS1 expression is upregulated following KRASG12D activation and may promote tumorigenesis and metastasis. Moreover, WFS1 expression was further elevated in tumors resistant to MRTX1133, independently of KRAS activation status. Inhibition of WFS1 partially restored sensitivity to MRTX1133 in resistant tumors by inducing excessive and sustained activation of the unfolded protein response (UPR), subsequently triggering apoptosis. Further exploration revealed that, while WFS1 is regulated by the MAPK and PI3K/AKT pathways in MRTX1133-sensitive cells, acquired resistance is associated with downregulation of the E3 ubiquitin ligase Smurf1, leading to increased WFS1 protein stability. Overall, these results highlight WFS1 as an adaptive factor and potential therapeutic target in KRASG12D-driven malignancies, offering a novel approach to enhance the efficacy of KRASG12D inhibitors and overcome acquired resistance.

DOI: https://doi.org/10.1038/s41698-026-01553-4
Soft Matter. 2026 Jun 19.

Pathways for fast and slow fusion of nanovesicles without membrane rupture.

Bartosz Różycki, Rikhia Ghosh, Reinhard Lipowsky.

Eukaryotic cells continuously remodel their membrane architecture by fusion processes, which are initiated by the adhesion of two membranes and eventually lead to a single membrane with a membrane neck or fusion pore. The fusion of cellular membranes involves membrane proteins but the fusion of biomimetic membranes such as lipid bilayers can be induced by bilayer tension even in the absence of proteins. Tension-induced fusion competes however with membrane rupture, which tends to impair the fusion process. Here, we show by molecular dynamics simulations that nanovesicles enclosed by tensionless and asymmetric bilayers can undergo fusion without rupture and that these fusion processes follow two distinct pathways, a slow and a fast one. Fast fusion starts immediately after an initial point contact between the two vesicles has been established whereas slow fusion occurs only after the vesicles have formed a spatially extended contact area. The two pathways are controlled by the stress asymmetry between the two bilayer leaflets or, equivalently, by the resulting transbilayer torque. Our simulation results have important consequences for the free energy landscapes corresponding to fast and slow fusion of nanovesicles, for experimental studies elucidating these fusion pathways, and for protein-mediated fusion of cellular membranes.

DOI: https://doi.org/10.1039/d6sm00288a