bims-cagime 2025-09-28 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–09–28
forty-two papers selected by
Kıvanç Görgülü, Technical University of Munich

Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses.
SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence.
Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.
An image analysis pipeline to quantify the spatial distribution of cell markers in stroma-rich tumors.
An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer.
Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
A consensus guide to preclinical indirect calorimetry experiments.
Emerging insights into lineage plasticity in pancreatic cancer initiation, progression, and therapy resistance.
Asymmetry-induced transient gel formation in fluid lipid membranes.
Spatial profiling of human pancreatic ductal adenocarcinoma reveals molecular alterations associated with venous invasion.
Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation.
Live-cell imaging with fluorogenic radical-trapping antioxidant probes reveals the onset and progression of ferroptosis.
Seipin Governs caveolin-1 trafficking through modulating sphingolipid-glycerolipid balance.
Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state.
Intrinsic heterogeneity of primary cilia revealed through spatial proteomics.
EML4-ALK variant-specific genetic interactions shape lung tumorigenesis.
Transport of sphingolipids by yeast Npc2 supports phase separation of the vacuole membrane.
The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution.
Entosis in Health and Disease.
For Better or Worse: The Impact of Necrotic Cell Death Modalities.
Unveiling the Gut-Pancreas Axis: Microbial Influence on Stemness and Tumor Microenvironment of PDAC.
Microscopy methods to visualize nuclear organization in biomechanical studies.
Multimodal AI-driven Biomarker for Early Detection of Cancer Cachexia.
Cancer-induced Nerve Injury Unveils a Sympathetic-to-Sensory Nerve Axis in Head and Neck Cancer.
Identification, functional insights and therapeutic targeting of EMT tumour states.
Collective migration: Galvanotaxis in field-tested teams.
SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer.
Semaglutide impacts skeletal muscle to a similar extent as caloric restriction in mice with diet-induced obesity.
V-ATPase-dependent induction of selective autophagy.
Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
Bifunctional Probes Reveal the Rules of Intracellular Ether Lipid Transport.
Atg4B-Activated Near-Infrared Nanoprobe for Precise Imaging of Autophagy In Vivo.
TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
Cellular elasticity drives the mechano-adaptation against fluid shear stress.
Design of a potent interleukin-21 mimic for cancer immunotherapy.
Organelle-specific signaling of cGAS-STING.
Comparison of imaging based single-cell resolution spatial transcriptomics profiling platforms using formalin-fixed paraffin-embedded tumor samples.
Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches.
A Mechanometabolism Toolbox for Studying Cell Migration.
Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice.
ScLineageAtlas: a comprehensive single-cell genomics database for characterizing cellular clones in cancer.

Cancer Cell. 2025 Sep 25. pii: S1535-6108(25)00395-2. [Epub ahead of print]

Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses.

Lei Ren, Chunfeng Liu, Kaan Çifcibaşı, Markus Ballmann, Gerhard Rammes, Carmen Mota Reyes, Sergey Tokalov, Andreas Klingl, Jennifer Grünert, Keshav Goyal, Peter H Neckel, Ulrich Mattheus, Benjamin Schoeps, Saliha Elif Yıldızhan, Osman Ugur Sezerman, Nedim Can Cevik, Elif Arik Sever, Didem Karakas, Okan Safak, Katja Steiger, Alexander Muckenhuber, Kıvanç Görgülü, Zongyao Chen, JingCheng Zhang, Linhan Ye, Mohammed Inayatullah Maula Ali, Vijay K Tiwari, Nataliya Romanyuk, Florian Giesert, Dieter Saur, Roland Rad, Roland M Schmid, Hana Algül, Achim Krüger, Helmut Friess, Güralp O Ceyhan, Rouzanna Istvanffy, Ihsan Ekin Demir.

  Cancers thrive on neuronal input. Here, we demonstrate the presence of pseudo-synaptic connections between sensory nerve endings and cancer cells in an extracerebral cancer, i.e., pancreatic ductal adenocarcinoma (PDAC). These synaptic sites exhibit a selective enrichment of the glutamatergic N-methyl-D-aspartate receptor (NMDA) receptor subunit NMDAR2D (GRIN2D) on the cancer cells, which turns PDAC cells responsive to neuron-derived glutamate and promotes tumor growth and spread. Intriguingly, neurons transform a subset of co-cultured PDAC cells into calcium-responsive cells via GRIN2D-type glutamate receptors at the neuron-cancer pseudo-synapses. We found that the expression of this subunit is due to the increased glutamate availability provided by sensory innervation in a neurotrophic feedforward loop. Moreover, interference with the glutamate-GRIN2D signaling at these neuron-cancer pseudo-synapses markedly improved survival in vivo. This discovery of peripheral cancer-neuron pseudo-synapses may provide an opportunity for cancer-neuroscience-instructed oncological therapies.

Keywords:  GRIN2D; L-glutamate; NMDAR; glutamatergic receptor; innervation; neural invasion; pancreatic cancer; synapse

DOI:  https://doi.org/10.1016/j.ccell.2025.09.003
Nat Cancer. 2025 Sep 25.

SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence.

Kaloyan M Tsanov, Francisco M Barriga, Yu-Jui Ho, Direna Alonso-Curbelo, Geulah Livshits, Sha Tian, Richard P Koche, Timour Baslan, Janelle Simon, Alexandra N Wuest, José Reyes, Jin Park, Wei Luan, John E Wilkinson, Umesh Bhanot, Jordana Ray-Kirton, Ignas Masilionis, Nevenka Dimitrova, Christine A Iacobuzio-Donahue, Ronan Chaligné, Dana Pe'er, Joan Massagué, Scott W Lowe.

The role of driver gene mutations in sustaining tumor growth at metastatic sites is poorly understood. SMAD4 inactivation is a paradigm of such mutations and a hallmark of pancreatic ductal adenocarcinoma (PDAC). To determine whether metastatic tumors are dependent on SMAD4 inactivation, we developed a mouse model of PDAC that enables spatiotemporal control of Smad4 expression. While Smad4 inactivation in the premalignant pancreas facilitated the formation of primary tumors, Smad4 reactivation in metastatic disease suppressed liver metastases but promoted lung metastases. These divergent effects were underpinned by organ-biased differences in the tumor cells' chromatin state that emerged in the premalignant pancreas and were distinguished by the dominance of KLF4 versus RUNX1 transcription factors. Our results show how epigenetic states favored by the organ of residence can influence the output of driver mutations in metastatic tumors, which has implications for interpreting tumor genetics and therapeutically targeting metastatic disease.

DOI: https://doi.org/10.1038/s43018-025-01047-5
bioRxiv. 2025 Sep 17. pii: 2025.09.15.676415. [Epub ahead of print]

Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia.

Bowen Xu, Aniket S Joshi, Meiricris Tomaz da Silva, Silin Liu, Ashok Kumar.

Cachexia is a debilitating syndrome marked by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrate that KPC tumor growth induces myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhances the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbates muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered novel intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, these results reveal previously unrecognized molecular mechanisms that regulate skeletal muscle homeostasis and identify potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.

DOI: https://doi.org/10.1101/2025.09.15.676415
Front Bioinform. 2025 ;5 1619790

An image analysis pipeline to quantify the spatial distribution of cell markers in stroma-rich tumors.

Antoine A Ruzette, Nina Kozlova, Kayla A Cruz, Taru Muranen, Simon F Nørrelykke.

  Aggressive cancers, such as pancreatic ductal adenocarcinoma (PDAC), are often characterized by a complex and desmoplastic tumor microenvironment, a stroma rich supportive connective tissue composed primarily of extracellular matrix (ECM) and non-cancerous cells. Desmoplasia, a dense deposition of stroma, is a major reason for therapy resistance, acting both as a physical barrier that interferes with drug penetration and as a supportive niche that protects cancer cells through diverse mechanisms. Precise understanding of spatial cell interactions in stroma-rich tumors is essential for optimizing therapeutic responses. It enables detailed mapping of stromal-tumor interfaces, comprehensive cell phenotyping, and insights into changes in tissue architecture, improving assessment of drug responses. Recent advances in multiplexed immunofluorescence imaging have enabled the acquisition of large batches of whole-slide tumor images, but scalable and reproducible methods to analyze the spatial distribution of cell states relative to stromal regions remain limited. To address this gap, we developed an open-source computational pipeline that integrates QuPath, StarDist, and custom Python scripts to quantify biomarker expression at a single- and sub-cellular resolution across entire tumor sections. Our workflow includes: (i) automated nuclei segmentation using StarDist, (ii) machine learning-based cell classification using multiplexed marker expression, (iii) modeling of stromal regions based on fibronectin staining, (iv) sensitivity analyses on classification thresholds to ensure robustness across heterogeneous datasets, and (v) distance-based quantification of the proximity of each cell to the stromal border. To improve consistency across slides with variable staining intensities, we introduce a statistical strategy that translates classification thresholds by propagating a chosen reference percentile across the distribution of marker-related cell measurement in each image. We apply this approach to quantify spatial patterns of distribution of the phosphorylated form of the N-Myc downregulated gene 1 (NDRG1), a novel DNA repair protein that conveys signals from the ECM to the nucleus to maintain replication fork homeostasis, and a known cell proliferation marker Ki67 in fibronectin-defined stromal regions in PDAC xenografts. The pipeline is applicable for the analysis of markers of interest in stroma-rich tissues and is publicly available.

Keywords:  Ki67; QuPath; fluorescence microscopy image; pNDRG1; pancreatic ductal adenocarcinoma cancer (PDAC); spatial analysis; stroma

DOI:  https://doi.org/10.3389/fbinf.2025.1619790
Nat Commun. 2025 Sep 26. 16(1): 8307

An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer.

Sara Söderqvist, Annika Viljamaa, Natalie Geyer, Anna-Lena Keller, Kseniya Ruksha, Carina Strell, Neda Hekmati, Alexandra Niculae, Jennie Engstrand, Ernesto Sparrelid, Caroline Salmén, Tânia D F Costa, Miao Zhao, Staffan Strömblad, Argyro Zacharouli, Poya Ghorbani, Sara Harrizi, Yousra Hamidi, Olga Khorosjutina, Stefina Milanova, Bernhard Schmierer, Béla Bozóky, Carlos Fernández Moro, Marco Gerling.

Pancreatic cancer is an aggressive disease with a dense fibrotic stroma and is often accompanied by chronic inflammation. Peritumoral inflammation is typically viewed as a reaction to nearby tumor growth. Here, we report that the inflamed pancreatic lobules are frequently invaded by tumor cells, forming a distinct, non-fibrotic tumor niche. Using a semi-supervised machine learning approach for annotations of clinical samples and multiplex protein profiling, we show that tumor cells at the invasion front are closely associated with acinar cells undergoing damage-induced changes, and with activated fibroblasts expressing markers of injury. The invaded lobules are linked to classical tumor phenotypes, in contrast to fibrotic areas where tumor cells display a more basal profile, highlighting microenvironment-dependent tumor subtype differences. In female mice, lobular invasion similarly aligns with the classical tumor phenotype. Together, our data reveal that pancreatic tumors colonize injured lobules, creating a unique niche that shapes tumor characteristics and contributes to disease biology.

DOI: https://doi.org/10.1038/s41467-025-63864-7
bioRxiv. 2025 Sep 20. pii: 2025.09.19.675739. [Epub ahead of print]

Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.

Alica K Beutel, Sabrina Calderon, Ethan Nghiem, Kevin Gulay, Leonor P S Santana, Eleni Zimmer, Rima Singh, Cecily Anaraki, Natalie Yousefian, Chantal Allgöwer, Gregory Tong, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy. However, resistance remains a major hurdle in clinical care. Resistance can arise from microenvironmental metabolites or through direct metabolic reprogramming of pancreatic cancer cells. Here, we generated PDAC models of acquired gemcitabine resistance to determine the relationship between these mechanisms. We observed that physiological levels of exogenous pyrimidines have a diminished ability to impact gemcitabine response in PDAC cells with acquired resistance. This occurs as the metabolic reprogramming of PDAC cells in response to gemcitabine treatment forces a suppression of the pyrimidine salvage pathway. Importantly, this metabolic rewiring renders gemcitabine-resistant PDAC cells highly susceptible to inhibition of the rate limiting enzyme of the mevalonate biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), using statins. Notably, statin treatment inhibits the growth of gemcitabine-resistant tumors in immunocompetent mouse models. Through metabolite rescue experiments, we identified geranylgeranyl pyrophosphate as the critical metabolite lost during statin treatment, resulting in reduced protein geranylation in PDAC cells. Finally, as downregulation of the HMGCR is gradually acquired during gemcitabine resistance, we observed that HMGCR expression predicts patient response to gemcitabine. Collectively, these data demonstrate that the mevalonate biosynthesis pathway represents a promising therapeutic target in gemcitabine resistance and may serve as a biomarker to stratify treatment selection in PDAC patients.

DOI: https://doi.org/10.1101/2025.09.19.675739
Nat Metab. 2025 Sep;7(9): 1765-1780

A consensus guide to preclinical indirect calorimetry experiments.

International Indirect Calorimetry Consensus Committee (IICCC)

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.

DOI: https://doi.org/10.1038/s42255-025-01360-4
Dev Cell. 2025 Sep 22. pii: S1534-5807(25)00440-X. [Epub ahead of print]60(18): 2391-2406

Emerging insights into lineage plasticity in pancreatic cancer initiation, progression, and therapy resistance.

Xintong Zhang, Yaru Du, Axel Behrens, Linxiang Lan.

  Lineage plasticity, the ability of cells to switch from one specialized identity to another, is a fundamental cellular process in embryonic development and tissue regeneration. The process is often hijacked by tumor cells at various stages to facilitate cancer initiation, progression, metastasis, and therapy resistance. It is also recognized as a key contributor to intratumor heterogeneity (ITH). In pancreatic ductal adenocarcinoma (PDAC), lineage plasticity is central to acinar-to-ductal metaplasia (ADM) and its associated acinar-to-ductal reprogramming (ADR), epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) regeneration, and molecular subtype rewiring. These mechanisms generate diverse lineage trajectories that shape PDAC development, progression, and therapeutic outcomes. In this review, we discuss how normal and tumor cells in the pancreatic epithelium acquire lineage plasticity and its implications for PDAC pathogenesis, ITH, metastasis, and therapy resistance. We also highlight recent discoveries suggesting potential therapeutic strategies targeting key regulators of lineage plasticity in PDAC.

Keywords:  acinar-to-ductal metaplasia; acinar-to-ductal reprogramming; cancer stem cell; epithelial-mesenchymal transition; intratumor heterogeneity; lineage plasticity; molecular subtype

DOI:  https://doi.org/10.1016/j.devcel.2025.07.002
bioRxiv. 2025 Sep 16. pii: 2025.09.11.674739. [Epub ahead of print]

Asymmetry-induced transient gel formation in fluid lipid membranes.

Emad Pirhadi, Xin Yong.

Compositional asymmetry is a defining feature of cellular membranes, controlling permeability, protein activity, cholesterol dynamics, and shape remodeling. This asymmetry can create a stress imbalance, with the two leaflets experiencing opposing tensions, though direct experimental measurement of leaflet stress remains challenging. Such a stress imbalance can compress one leaflet and trigger a fluid-to-gel phase transition, which reduces membrane fluidity and markedly increases bending rigidity. These phenomena raise a key question of how membranes respond mechanically before crossing the transition threshold, a regime that remains relevant to biological functions. Here, we combine extensive all-atom and coarse-grained molecular dynamics simulations to examine how stress asymmetry modulates membrane structure and mechanics near the transition point. Using POPE and DLPC bilayers as model systems, we find that moderate asymmetry induces transient gel-like domains that continuously form and dissolve, amplifying undulations and lowering bilayer rigidity. Beyond the gelation threshold, the trend reverses and the bilayer stiffens, resulting in a non-monotonic dependence of rigidity on asymmetry. Moreover, our results reveal distinct curvature preferences of fluid and gel phases. Extending this analysis to a multicomponent bacterial outer membrane, we demonstrate that stress asymmetry can trigger transient gel-like domain formation even in complex lipid mixtures. This provides a proof of principle that differential stress modulates membrane mechanics by inducing either softening or stiffening, complementing the effects of molecular composition. Our findings elucidate how cells might exploit the stress-curvature-phase coupling to tune membrane rigidity under near-physiological conditions.

DOI: https://doi.org/10.1101/2025.09.11.674739
Sci Transl Med. 2025 Sep 24. 17(817): eady7524

Spatial profiling of human pancreatic ductal adenocarcinoma reveals molecular alterations associated with venous invasion.

Alexander T F Bell, Peter Chianchiano, Katsuya Hirose, Daniel Salas-Escabillas, Doreen M Zucha, Jacob T Mitchell, Ludmila Danilova, Alexander I Damanakis, Joseph A Tandurella, Jeanette Johnson, Jing Zhu, James R Eshleman, Qingfeng Zhu, Robert A Anders, Luciane T Kagohara, Elana J Fertig, Laura D Wood.

In pancreatic ductal adenocarcinoma (PDAC), venous invasion (VI) is a critical step in metastasis and is associated with poor survival. However, little is known about the molecular features of VI. To investigate, we performed spatial transcriptomic analysis of 95 human PDAC tissue samples from eight treatment-naïve patients. Our analysis revealed that, compared with PDAC in stroma, PDAC with VI demonstrated up-regulation of genes associated with epithelial differentiation, classical subtype, and benign exocrine function. Conversely, PDAC with VI demonstrated down-regulation of genes associated with mesenchymal differentiation, basal-like subtype, and disease aggression. Additionally, we uncovered characteristics of VI morphology that correlated with these molecular features. VI-intraepithelial neoplasia-like foci had preserved venous architecture and had a classical, epithelial molecular phenotype, whereas VI-destructive foci had destroyed venous architecture and had a more basal-like, mesenchymal phenotype. We contextualized our findings using public RNA-seq data and observed that metastatic PDAC had greater similarity to PDAC in stroma than to PDAC with VI, whereas circulating tumor cells showed no preferential association. We confirmed our findings by spatial proteomic analysis of VI in an independent cohort of 19 treatment-naïve patients with PDAC. Overall, our work provides a reference atlas of spatial transcriptomics and proteomics of VI in PDAC and reveals unexpected increases in molecular features associated with better patient outcomes.

DOI: https://doi.org/10.1126/scitranslmed.ady7524
Nature. 2025 Sep 24.

Ribonucleotide incorporation into mitochondrial DNA drives inflammation.

Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.

Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.

DOI: https://doi.org/10.1038/s41586-025-09541-7
bioRxiv. 2025 Sep 18. pii: 2025.09.16.676456. [Epub ahead of print]

VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation.

Sung-Hyun Hwang, Mingyun Bae, Ji-Won Kim, Seung Yoon Hyun, Kui-Jin Kim, Joshua H Choe, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Songji Choi, Woochan Park, Jeongmin Seo, Heejung Chae, Minsu Kang, Eun Hee Jung, Koung Jin Suh, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Haeseong Park, Andrew J Aguirre, Eunjung Alice Lee, Ja-Lok Ku, Keun-Wook Lee.

KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent studies have characterized features associated with primary and acquired resistance to KRAS inhibitors, strategies to overcome such resistance, particularly in the context of gastrointestinal cancers, remain underexplored. Here, we have generated nine human gastrointestinal cancer models, including three patient-derived organoids (PDOs), with acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. Using single-cell RNA sequencing analysis, we identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) signatures in the resistant model compared to the parental PDO. Across all resistant models, VEGFA expression and VEGFR2 phosphorylation were uniformly elevated, which were driven by AKT activation and SP1 nuclear translocation. Mechanistic investigations uncovered increased PI3Kγ activity in MRTX1133-resistant models via complex formation of KRAS with p110γ and p101. This leads to an autocrine VEGFA-VEGFR2 signaling loop formation and EMT induction. Therapeutically, the disruption of VEGFA-VEGFR2 signaling restored MRTX1133 sensitivity and inhibited EMT. Furthermore, cancer-endothelial paracrine signaling amplified angiogenesis, hypoxia, and EMT signatures in cancer cells and simultaneously promoted endothelial cell proliferation, reinforcing an adaptive feedback mechanism. In a mouse model of MRTX1133-resistant tumor xenograft, a combination of anti-VEGFR2 therapy and MRTX1133 more effectively reduced tumor growth, angiogenesis, and proliferation markers than monotherapy without significant body weight change. These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers.
Highlight: VEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRAS G12D cancer cells Nuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant modelsInteraction of p110γ-p101 with KRAS activates PI3Kγ in the resistant models VEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo.

DOI: https://doi.org/10.1101/2025.09.16.676456
Nat Chem. 2025 Sep 26.

Live-cell imaging with fluorogenic radical-trapping antioxidant probes reveals the onset and progression of ferroptosis.

Laiyi Xu, Wenzhou Zhang, Juan F Sánchez Tejeda, Denys Holovan, Julia McCain, Terri C Lovell, Gonzalo Cosa.

Ferroptosis is a form of cell death involving the formation of lipid peroxyl radicals, with potential therapeutic applications. Sensitivity to ferroptosis is expected to vary in different organelles. To monitor in real time the onset and progression of lipid peroxidation in ferroptosis, here we report lipophilic fluorogenic radical-trapping antioxidants, embedding in endoplasmic reticulum, lysosomes, mitochondria and plasma membrane. We show that endoplasmic reticulum- and lysosome-embedding fluorogenic radical-trapping antioxidants are most effective in protecting from cell death. The onset of lipid peroxidation happens in the endoplasmic reticulum, with lipid hydroperoxide accumulating in Golgi-associated vesicles. Disintegration of these structures spreads lipid hydroperoxide intracellularly, acting as 'free radical embers'. Outwards migration of oxidized lipids to plasma membrane, the ultimate sink for oxidized lipids, was recorded. Our results underscore Golgi-associated structures as a site to regulate ferroptosis progression. The work further positions fluorogenic radical-trapping antioxidants as valuable tools for unravelling the dynamic subcellular progression of ferroptosis.

DOI: https://doi.org/10.1038/s41557-025-01966-x
Cell Rep. 2025 Sep 22. pii: S2211-1247(25)01091-5. [Epub ahead of print]44(10): 116320

Seipin Governs caveolin-1 trafficking through modulating sphingolipid-glycerolipid balance.

Maxime Carpentier, Mohyeddine Omrane, Rola Shaaban, Jennica Träger, Naïma El Khallouki, Soazig Le Lay, Julie Patat, Marie Palard, Mehdi Zouiouich, Yoann Combot, Takeshi Harayama, Corinne Vigouroux, Kristine Schauer, Francesca Giordano, Xavier Prieur, Abdou Rachid Thiam.

  Dysregulation of caveolin-1 (CAV1), a core component of caveolae, causes pleiotropic disorders; yet, the mechanisms governing its trafficking remain poorly understood. Here, we show that the lipid droplet (LD) biogenesis factor seipin regulates CAV1 localization. Seipin deficiency in mice and HeLa cells resulted in the accumulation of saturated lipids and ceramides, thereby disrupting the membrane order of the trans-Golgi network (TGN). This impaired CAV1 trafficking to the plasma membrane, reduced caveolae formation, and redirected CAV1 to LDs-an effect also observed in seipin-deficient patient fibroblasts. We reproduced this phenotype in wild-type cells by supplementing them with palmitate or ceramide or by inhibiting stearoyl-CoA desaturase 1, indicating that saturated lipids' accumulation is the root cause. Conversely, blocking fatty acid synthase in seipin knockout cells restored proper CAV1 localization. Our findings suggest that seipin regulates lipid fluxes between glycerolipids and sphingolipids, which is critical for TGN integrity and CAV1 sorting.

Keywords:  CP: Cell biology; CP: Metabolism; TGN; caveolin 1; ceramide; glycerolipids; lipid droplet; lipid metabolism; lipodystrophy; membrane order; palmitate; protein trafficking; seipin; sphingolipids

DOI:  https://doi.org/10.1016/j.celrep.2025.116320
Cell Rep. 2025 Sep 22. pii: S2211-1247(25)01079-4. [Epub ahead of print]44(10): 116308

Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state.

Mirjam C van der Net, Marjolein J Vliem, Lars J S Kemp, Carlos Perez-Gonzalez, Tariq S Haddad, Esther A Strating, Ana Krotenberg-Garcia, Ronja M Houtekamer, Willem-Jan Pannekoek, Karen B van den Anker, Susan Zwakenberg, Jooske L Monster, Suzanne E M van der Horst, Hugo J G Snippert, Antoine A Khalil, Jacco van Rheenen, Saskia J E Suijkerbuijk, Onno Kranenburg, Femke Simmer, Iris D Nagtegaal, Danijela Matic Vignjevic, Martijn Gloerich.

  Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site and seeding liver metastases are devoid of Lgr5 expression. Using CRC organoid models, we demonstrate that mechanical interactions with collagen I, a main constituent of the interstitial matrix, instruct the reprogramming of CRC cells. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a cellular state with transcriptional similarities to fetal intestinal cells. CRC cells infiltrating the interstitial stroma show upregulation of this fetal-like transcriptional program, which correlates with the ability of Lgr5-negative cells to initiate metastasis formation. Our findings indicate that mechanical interactions with collagen I regulate cell fate transitions associated with the metastatic cascade of CRC.

Keywords:  CP: Cancer; CP: Cell biology; Lgr5; TRPV4; YAP1; cancer stem cell; colorectal cancer; fetal-like state; integrins; mechanosensitive calcium channels; mechanotransduction

DOI:  https://doi.org/10.1016/j.celrep.2025.116308
Cell. 2025 Sep 25. pii: S0092-8674(25)01029-3. [Epub ahead of print]

Intrinsic heterogeneity of primary cilia revealed through spatial proteomics.

Jan N Hansen, Huangqingbo Sun, Konstantin Kahnert, Eini Westenius, Alexandra Johannesson, Carmela Villegas, Trang Le, Kalliopi Tzavlaki, Casper Winsnes, Emmie Pohjanen, Anna Mäkiniemi, Jenny Fall, Frederic Ballllosera Navarro, Anna Bäckström, Cecilia Lindskog, Fredric Johansson, Kalle von Feilitzen, Angelica M Delgado-Vega, Anna Martinez Casals, Diana Mahdessian, Mathias Uhlén, Shu-Hsien Sheu, Anna Lindstrand, Ulrika Axelsson, Emma Lundberg.

  Primary cilia are critical organelles found on most human cells. Their dysfunction is linked to hereditary ciliopathies with a wide phenotypic spectrum. Despite their significance, the specific roles of cilia in different cell types remain poorly understood due to limitations in analyzing ciliary protein composition. We employed antibody-based spatial proteomics to expand the Human Protein Atlas to primary cilia. Our analysis identified the subciliary locations of 715 proteins across three cell lines, examining 128,156 individual cilia. We found that 69% of the ciliary proteome is cell-type specific, and 78% exhibited single-cilia heterogeneity. Our findings portray cilia as sensors tuning their proteome to effectively sense the environment and compute cellular responses. We reveal 91 cilia proteins and found a genetic candidate variant in CREB3 in one clinical case with features overlapping ciliopathy phenotypes. This open, spatial cilia atlas advances research on cilia and ciliopathies.

Keywords:  3D images; cell-type specificity; cellular heterogeneity; cilia; ciliopathies; immunofluorescence microscopy; primary cilia; signaling; signaling microdomains; spatial proteomics

DOI:  https://doi.org/10.1016/j.cell.2025.08.039
Cancer Discov. 2025 Sep 23.

EML4-ALK variant-specific genetic interactions shape lung tumorigenesis.

Alberto Diaz-Jimenez, Emily G Shuldiner, Kalman Somogyi, Karen Shih, Oscar Gonzalez-Velasco, Mulham Najajreh, Stewart Kim, Filiz Akkas, Christopher W Murray, Laura Andrejka, Min K Tsai, Benedikt Brors, Ilse Hofmann, Smruthy Sivakumar, Saumya D Sisoudiya, Ethan S Sokol, Hongchen Cai, Dmitri A Petrov, Monte M Winslow, Rocio Sotillo.

Diverse fusions of EML4 and ALK are oncogenic drivers in lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. Here, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes rather than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion-driven cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1417
bioRxiv. 2025 Sep 17. pii: 2025.09.14.676161. [Epub ahead of print]

Transport of sphingolipids by yeast Npc2 supports phase separation of the vacuole membrane.

Hyesoo Kim, Nicolas-Frédéric Lipp, Israel Juarez-Contreras, Adrian M Wong, Itay Budin.

The yeast vacuole membrane forms ordered microdomains that facilitate micro-lipophagy under nutrient limitation. We previously found that this process involves the intracellular sorting of sphingolipids to the vacuole. While multiple vacuole protein pathways have been identified, corresponding mechanisms for lipid sorting remain undefined. Here we use a range of approaches to identify how endocytic sorting and intraluminal transport of sphingolipids contribute to the formation of vacuole domains. To visualize sphingolipid trafficking, we employed the ceramide analogue BODIPY C12-ceramide (BODIPY-Cer), which is internalized by cells and stains the vacuole. We observed that cells lacking Vps29 and Vps30, proteins involved in endosomal sorting, show altered vacuole domains and accumulate BODIPY-Cer at sites proximal to the plasma membrane. Subsequent incorporation of endocytic-derived ceramide into the vacuole is dependent on the Niemann-Pick Type C 2 protein (Npc2). Loss of Npc2 reduces domain formation and causes BODIPY-Cer to accumulate within the vacuole lumen. Both intra-vacuole trafficking of BODIPY-Cer and membrane phase separation were not dependent on Npc2's canonical receptor, Ncr1. Lipidomics of isolated vacuoles confirmed that Npc2 independently mediates sphingolipid sorting under micro-lipophagy conditions. In liposome assays, Npc2 robustly transports analogues of ceramide and inositol phosphorylceramide, a complex sphingolipid that is enriched in phase-separated vacuoles. We propose that the enlarged binding cavity of yeast Npc2 is specialized for the incorporation of sphingolipids into the vacuole membrane.

DOI: https://doi.org/10.1101/2025.09.14.676161
Nature. 2025 Sep;645(8082): 877-885

The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution.

Biodiversity Cell Atlas meeting participants

Cell types are fundamental functional units that can be traced across the tree of life. Rapid advances in single-cell technologies, coupled with the phylogenetic expansion in genome sequencing, present opportunities for the molecular characterization of cells across a broad range of organisms. Despite these developments, our understanding of eukaryotic cell diversity remains limited and we are far from decoding this diversity from genome sequences. Here we introduce the Biodiversity Cell Atlas initiative, which aims to create comprehensive single-cell molecular atlases across the eukaryotic tree of life. This community effort will be phylogenetically informed, rely on high-quality genomes and use shared standards to facilitate comparisons across species. The Biodiversity Cell Atlas aspires to deepen our understanding of the evolution and diversity of life at the cellular level, encompassing gene regulatory programs, differentiation trajectories, cell-type-specific molecular profiles and inter-organismal interactions.

DOI: https://doi.org/10.1038/s41586-025-09312-4
Adv Exp Med Biol. 2025 ;1481 293-303

Entosis in Health and Disease.

Jyotirekha Das, Michael Overholtzer.

  Entosis is a mechanism of cell-in-cell formation that resembles phagocytosis but is regulated by distinct processes related to cell-cell adhesion and actomyosin tension. Entosis results in the engulfment of cells with high levels of tension, which become internalized into cells with lower tension, following the formation of adherens junctions between the pair. The resulting "cell-in-cell" structures typically resolve in a manner that leads to the death of the internalized cells, although other fates, including internalized cell release, are also possible. Entosis is induced in response to a variety of stressors, sometimes in parallel to other forms of cell death, and has been observed to occur in cancer as well as normal tissues. Here we discuss the mechanism of entosis and consider its unique properties compared to other forms of cell death and engulfment.

Keywords:  Adherens junctions; Autophagy; E-cadherin; Entosis; Entotic cell death; Lysosome; ROCK; Rho

DOI:  https://doi.org/10.1007/978-3-031-92785-0_9
Adv Exp Med Biol. 2025 ;1481 241-292

For Better or Worse: The Impact of Necrotic Cell Death Modalities.

Peter Vandenabeele, Marcus Conrad, Adam Wahida.

  Cellular stress, infection, and inflammation lead to various forms of cell death. Depending on the stimulus, cell type, and cellular conditions, different modes of regulated cell death might be engaged. These include apoptosis, necroptosis, and pyroptosis, which are driven by genetically programmed mechanisms, and ferroptosis, a type of metabolic cell death. The outcome of these distinct cell death modalities is the activation of specific pore-forming mechanisms: caspase-3-mediated cleavage of gasdermin E in secondary necrosis following apoptosis (also classified as pyroptosis), RIPK3-mediated phosphorylation of MLKL in necroptosis, and caspase-1/11/4/5-mediated cleavage of GSDMD during pyroptosis. In the case of ferroptosis, a metabolic cell death modality driven by imbalances in iron, lipid, and redox metabolism, the plasma membrane also becomes permeabilized due to oxidative modifications of acyl chains in phospholipids. On top of the pore-forming mechanisms, NINJ1 detects cellular swelling ("oncosis") and triggers a massive plasma membrane rupture as a final stage of the cellular cataclysm, releasing large molecules and intracellular contents. Understanding the mechanisms of regulated necrotic cell death through signaling pathways or by disrupting metabolic networks offers tangible targeting strategies to enhance or reduce cell death processes and associated subroutines in various diseases, including cancer, ischemia/reperfusion conditions, inflammation, and degenerative diseases. Besides the molecular biology, we will concentrate this chapter on the effects of necroptosis, pyroptosis, and ferroptosis in cancer and inflammatory pathologies in the brain, intestine, and skin.

Keywords:  Ferroptosis; GSDM; MLKL; Metabolic cell death; NINJ1; Necroptosis; Necrotic cell death in cancer; Necrotic cell death in pathological immunity; Pyroptosis; Regulated necrotic cell death

DOI:  https://doi.org/10.1007/978-3-031-92785-0_8
Stem Cells. 2025 Sep 27. pii: sxaf064. [Epub ahead of print]

Unveiling the Gut-Pancreas Axis: Microbial Influence on Stemness and Tumor Microenvironment of PDAC.

Kirtana Arikath, Surinder K Batra, Moorthy P Ponnusamy.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and malignant cancer of the pancreas characterized by various genetic mutations and metabolic dysregulations. Stem cells play a critical role in the initiation, progression, and resistance of PDAC due to their plasticity, self-renewal capabilities, and ability to drive tumorigenesis. The gut microbiome, a diverse ecosystem of microorganisms, has a profound influence on systemic health, including the development of cancer. Recent studies have highlighted that the microbiome composition within the tumor can modulate stem cell behavior by shaping the tumor microenvironment (TME), enhancing cellular plasticity, and promoting the stemness properties of PDAC. In this review, we explore the potential crosstalk between the gut microbiome and PDAC stem cells, focusing on how microbiome-derived signals impact stem cell maintenance, inflammation, metastasis, TME modulation, and metabolic reprogramming.

Keywords:  Cancer; Cancer stem cells; Microenvironment; Pancreas; Stem cell-microenvironment interactions

DOI:  https://doi.org/10.1093/stmcls/sxaf064
Curr Opin Biomed Eng. 2024 Jun;pii: 100528. [Epub ahead of print]30

Microscopy methods to visualize nuclear organization in biomechanical studies.

Hannah Hyun-Sook Kim, Melike Lakadamyali.

The mechanical environment plays an important role in influencing cell identity. The nucleus's organization and mechanical state are essential regulators of cellular function. However, open questions remain about the mechanisms underlying how the physical microenvironment influences nuclear mechanics and organization to drive specific transcriptional and epigenetic shifts. Understanding how biophysical cues change cell behavior provides groundwork to improve medical technologies such as tissue engineering, stem cell therapy, and mitigation of aberrant cell behavior. Microscopy is an indispensable tool that noninvasively explores the cell's nuclear state, providing valuable measurements on features including nuclear morphology, nuclear mechanical properties, protein localization, and genomic organization. In this review, we discuss notable imaging techniques, such as super-resolution microscopy, examples of how they have recently advanced the field, and how they can further our knowledge of the interplay between nuclear mechanoregulation and cell function.

DOI: https://doi.org/10.1016/j.cobme.2024.100528
medRxiv. 2025 Sep 19. pii: 2025.09.17.25336028. [Epub ahead of print]

Multimodal AI-driven Biomarker for Early Detection of Cancer Cachexia.

Sabeen Ahmed, Nathan Parker, Margaret Park, Evan W Davis, Daniel Jeong, Jennifer B Permuth, Matthew B Schabath, Yasin Yilmaz, Ghulam Rasool.

Cancer cachexia, a multifactorial metabolic syndrome characterized by severe muscle wasting and weight loss, contributes to poor outcomes across various cancer types but lacks a standardized, generalizable biomarker for early detection. We present a multimodal AI-based biomarker trained on real-world clinical, radiologic, laboratory, and unstructured clinical note data, leveraging foundation models and large language models (LLMs) to identify cachexia at the time of cancer diagnosis. Prediction accuracy improved with each added modality: 77% using clinical variables alone, 81% with added laboratory data, and 85% with structured symptom features extracted from clinical notes. Incorporating embeddings from clinical text and CT images further improved accuracy to 92%. The framework also demonstrated prognostic utility, improving survival prediction as data modalities were integrated. Designed for real-world clinical deployment, the framework accommodates missing modalities without requiring imputation or case exclusion, supporting scalability across diverse oncology settings. Unlike prior models trained on curated datasets, our approach utilizes standard-of-care clinical data, facilitating integration into oncology workflows. In contrast to fixed-threshold composite indices such as the cachexia index (CXI), the model generates patient-specific predictions, enabling adaptable, cancer-agnostic performance. To enhance clinical reliability and safety, the framework incorporates uncertainty estimation to flag low-confidence cases for expert review. This work advances a clinically applicable, scalable, and trustworthy AI-driven decision support tool for early cachexia detection and personalized oncology care.

DOI: https://doi.org/10.1101/2025.09.17.25336028
bioRxiv. 2025 Sep 19. pii: 2025.09.19.677339. [Epub ahead of print]

Cancer-induced Nerve Injury Unveils a Sympathetic-to-Sensory Nerve Axis in Head and Neck Cancer.

Andre A Martel Matos, Lisa A McIlvried, Nicole L Horan, Nicole A Rodriguez, Jared I Rothberg, Megan A Atherton, Stephen V Glass, Marci L Nilsen, Nicole N Scheff.

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, with patients frequently reporting spontaneous, neuropathic-like pain. While sympathetic and sensory nerves have been individually implicated in cancer progression, whether and how these systems interact to drive pain and tumor growth has remained unclear. Here, we integrate prospective human data with reverse-translational mouse models to reveal that cancer-induced nerve injury unveils crosstalk between sympathetic postganglionic neurons and trigeminal sensory afferents in the tumor microenvironment. In patients, circulating norepinephrine (NE) correlated with spontaneous pain and perineural invasion, identifying a potential sympathetic contribution to disease burden. In mice, aggressive non-immunogenic OSCC tumors evoked spontaneous nociceptive behaviors, elevated tumoral NE, and sensory nerve injury marked by ATF3 expression and hyperexcitability. Tumor-associated sensory neurons acquired adrenergic sensitivity through α1-adrenergic receptor plasticity, while sympathetic neurons exhibited plasticity characterized by sprouting, altered gene expression, and heightened excitability, creating a maladaptive feed-forward loop that amplified nociceptive signaling. Disrupting this sympathetic-sensory communication by sympathectomy or selective ablation of TRPV1⁺ sensory fibers reduced tumor growth, sympathetic tone, and spontaneous pain like behaviors, although sensory adrenergic sensitivity persisted. Together, these findings establish that reciprocal sympathetic-sensory plasticity and crosstalk in the tumor may fuel both OSCC progression and neuropathic like pain. Targeting this peripheral neuroplasticity may offer a translational strategy to limit tumor growth and alleviate pain.

DOI: https://doi.org/10.1101/2025.09.19.677339
Nat Rev Cancer. 2025 Sep 25.

Identification, functional insights and therapeutic targeting of EMT tumour states.

Anqi Dong, Cédric Blanpain.

Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed.

DOI: https://doi.org/10.1038/s41568-025-00873-0
Curr Biol. 2025 Sep 22. pii: S0960-9822(25)01027-9. [Epub ahead of print]35(18): R880-R883

Collective migration: Galvanotaxis in field-tested teams.

Lucija Mijanovic, Robert H Insall.

Electric fields steer cell movement. A recent study reports that individual cells and groups of cells sense the field's direction in different ways, illuminating the core mechanics of collective migration.

DOI: https://doi.org/10.1016/j.cub.2025.07.082
Nature. 2025 Sep 24.

SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer.

Huafu Li, Linxiang Lan, Hengxing Chen, May Zaw Thin, Hari Ps, Jessica K Nelson, Ian M Evans, E Josue Ruiz, Rongjie Cheng, Li Tran, Mark Allen, Jian Ma, Tingzhuang Yi, Chunming Wang, Yulong He, Naomi Guppy, Anguraj Sadanandam, Shao-Zhen Lin, Changhua Zhang, Axel Behrens.

Elucidating the complex network of communication between tumour cells is central to understanding cell fate decisions and progression of pancreatic ductal adenocarcinoma (PDAC)1,2. We previously showed that constant suppression of BMP activity by the BMP antagonist GREM1 secreted by mesenchymal PDAC cells is essential for maintaining the fate of epithelial PDAC cells3. Here we identify SPP1 (also known as osteopontin)4 as a key regulator of mesenchymal cell fate in pancreatic cancer. Proteomic analysis of plasma from patients with PDAC showed that SPP1 is substantially upregulated in late-stage disease. Inactivation of Spp1 led to a delay in tumorigenesis in mouse PDAC models and abolished metastasis formation. Spp1 was expressed in epithelial PDAC cells, and Spp1 inactivation resulted in a conversion of mesenchymal to epithelial PDAC cells. Mechanistically, SPP1 bound the CD61 receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression, and GREM1 inhibition of BMP signalling was required for Spp1 expression in epithelial cells, thereby forming an intercellular regulatory loop. Concomitant inactivation of Grem1 reverted the epithelial phenotype of Spp1 knockout to fully mesenchymal PDAC. Conversely, Grem1 heterozygosity combined with Spp1 knockout resulted in wild-type PDAC histology, a result that confirmed the direct antagonistic functions of these factors. Hence, mesenchymal and epithelial PDAC cell fates are determined by the reciprocal paracrine regulation of the soluble factors GREM1 and SPP1.

DOI: https://doi.org/10.1038/s41586-025-09574-y
J Physiol. 2025 Sep 22.

Semaglutide impacts skeletal muscle to a similar extent as caloric restriction in mice with diet-induced obesity.

S Jeromson, B Baranowski, M Akcan, B D Waters, K Eisner, A Bellucci, S Trang, A Abolhassani, M A Tello-Palencia, A Schweitzer, B Stefanska, C J Mitchell, David C Wright.

  Semaglutide is a GLP-1 receptor agonist that is highly efficacious in reducing food intake and body weight. While semaglutide reduces adipose tissue, there is also a loss of lean mass including skeletal muscle, though it is unclear whether this translates to a loss of muscle function. The effect of discontinuation of semaglutide on rebound weight gain and shifts in body composition is also not well understood. We investigated the impact of semaglutide and matched caloric restriction on body composition in mice with diet-induced obesity. Mice were treated with semaglutide or fed a calorie-matched diet for 4 weeks. Semaglutide and pair-feeding induced significant weight loss with a concomitant reduction in energy expenditure. Weight loss was greater with semaglutide than caloric restriction, despite matched energy intake. Muscle transcriptomic analyses revealed distinct molecular responses between semaglutide and pair-feeding. In a follow-up experiment, semaglutide and pair-feeding was discontinued after 4 weeks, and body weight and food intake were tracked for 6 weeks. At the end of the withdrawal period there was a loss of treatment effects. Lean and fat mass rebounded to baseline levels at the end of the withdrawal period. Muscle size and strength were also comparable between groups. These findings demonstrate that semaglutide reduces muscle size and strength to the same extent as caloric restriction but may be more effective at promoting fat loss. Interestingly, the loss of lean mass and skeletal muscle recovered following treatment discontinuation. KEY POINTS: Semaglutide results in greater weight loss than caloric restriction. Semaglutide treatment increases fat loss compared with caloric restriction. Muscle mass and strength is reduced to a similar extent by semaglutide and restricted feeding.

Keywords:  obesity; semaglutide; skeletal muscle; weight loss

DOI:  https://doi.org/10.1113/JP289449
Nat Commun. 2025 Sep 26. 16(1): 8508

V-ATPase-dependent induction of selective autophagy.

Yuxiang Huang, Dimitra Dialynaki, Yuchen Lei, Zhihai Zhang, Charles R Evans, Daniel J Klionsky.

The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain unclear. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed "V-ATPase-dependent autophagy ". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that V-ATPase-dependent autophagy is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates V-ATPase-dependent autophagy via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide an explanation for the mutational activation of autophagy seen in follicular lymphoma patients.

DOI: https://doi.org/10.1038/s41467-025-63472-5
Nat Cardiovasc Res. 2025 Sep 24.

Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.

Sumeet A Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L Smythers, Katherine A Blackmore, Louisa Grauvogel, Melanie J Mittenbühler, Melin J Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E Houstis, Hans-Georg Sprenger, Sean J Jurgens, Kiran J Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T Ellinor, Matthias Nahrendorf, Joao A Paulo, Steven P Gygi, Phillip A Dumesic, Aarti Asnani, Krishna G Aragam, Pere Puigserver, Jason D Roh, Bruce M Spiegelman, Anthony Rosenzweig.

Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.

DOI: https://doi.org/10.1038/s44161-025-00712-3
Angew Chem Int Ed Engl. 2025 Sep 21. e202513360

Bifunctional Probes Reveal the Rules of Intracellular Ether Lipid Transport.

Kristin Böhlig, Juan Manuel Iglesias-Artola, Antonino Asaro, H Mathilda Lennartz, Anna C Link, Björn Drobot, André Nadler.

  Ether glycerophospholipids bear a long chain alcohol attached via an alkyl or vinyl ether bond at the sn1 position of the glycerol backbone. Ether lipids play a significant role in physiology and human health. However, their cellular functions remain largely unknown due to a lack of tools for identifying their subcellular localization and interacting proteins. Here, we address this methodological gap by synthesizing minimally modified bifunctional ether lipid probes by introducing diazirine and alkyne groups. To interrogate the subcellular kinetics of intracellular ether lipid transport in mammalian cells, we used a combination of fluorescence imaging, machine learning-assisted image analysis, and mathematical modelling. We find that alkyl-linked ether lipids are transported up to twofold faster than vinyl-linked species (plasmalogens), pointing to yet undiscovered cellular lipid transport machinery able to distinguish between linkage types differing by as little as two hydrogen atoms. We find that ether lipid transport predominantly occurs via non-vesicular pathways, with varying contributions from vesicular mechanisms between cell types. Altogether, our results suggest that differential recognition of alkyl- and vinyl ether lipids by lipid transfer proteins contributes to their distinct biological functions. In the future, the probes reported here will enable studying ether lipid biology in much greater detail through identification of interacting proteins and in-depth characterization of intracellular ether lipid dynamics.

Keywords:  Bifunctional lipids; Ether lipids; Lipid imaging; Lipid transport; Plasmalogens

DOI:  https://doi.org/10.1002/anie.202513360
Anal Chem. 2025 Sep 23.

Atg4B-Activated Near-Infrared Nanoprobe for Precise Imaging of Autophagy In Vivo.

Xiaotong Cheng, Tiantian Xia, Guowei Liang, Hai-Dong Xu, Xiaoyang Liu, Gaolin Liang.

Autophagy plays a crucial role in maintaining cellular homeostasis, and its dysregulation is implicated in various diseases. High-precision imaging of autophagy activity in deep tissues is vital for elucidating the mechanisms of autophagy-related disorders, yet existing near-infrared (NIR) fluorescent probes often lack sufficient accuracy. To overcome this limitation, we developed an Atg4B-activated NIR nanoprobe for highly selective detection of autophagy. The "dual quenched" fluorescent probe, IR780-CBT NP, was synthesized via a CBT-Cys click condensation reaction using the fluorescent precursor Cys(StBu)-Thr-Phe-Gly-Lys(IR780)-CBT (IR780-CBT) under reducing conditions. Upon cellular uptake by autophagy-active cells, Atg4B-specific hydrolysis induces disassembly of IR780-CBT NPs, restoring NIR fluorescence. In autophagy-activated MDA-MB-231 cells and tumor-bearing mice, IR780-CBT NPs exhibited 4.5-fold and 3.1-fold enhanced fluorescence signals, respectively, compared to the "RAPA + Inh."-treated controls. These findings highlight the potential of IR780-CBT NPs for precise autophagy imaging in vivo, offering a promising tool for early diagnosis and mechanistic studies of autophagy-related diseases.

DOI: https://doi.org/10.1021/acs.analchem.5c03954
bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.

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

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

DOI: https://doi.org/10.1101/2025.09.11.675705
J Cell Sci. 2025 Sep 26. pii: jcs.264293. [Epub ahead of print]

Cellular elasticity drives the mechano-adaptation against fluid shear stress.

Ditipriya Mallick, Indranil Ghosh, Tanmoy Mondal, Sourav Mondal, Rupa Mukhopadhyay, Jomon Joseph, Somiranjan Ghosh, Siddhartha Sankar Jana.

  Cancer cells adapt to external biophysical cues but how the cytoskeletal remodeling facilitate this mechano-adaptation is largely unexplored. Here, we demonstrate that the intrinsic non-muscle myosinII (NMII) activity and self-organization in cancer cells regulate the cellular elastic property when cells are exposed to fluid shear stress (FSS). In association with the reorganized actin filament network, NMII bipolar filaments can assemble into aligned stacks, which allow cellular stretching upon exposure to FSS. Inhibition of NMIIs by siRNA, (-) blebbistatin or Y27632 impairs the stack formation and perturbs cellular elasticity. Moreover, NMII-mediated elasticity regulates cyto-nuclear coupling through its association with LINC complex protein, Nesprin-2, and regulates nuclear import of the mechanoresponsive proteins, YAP/TAZ, which induce differential expression of genes thus decreasing growth and migration in FSS-exposed cells. These findings reveal that the cellular elasticity mediated by NMII dynamics provides mechano-adaptation against a mechanical stress, like FSS.

Keywords:  Cellular elasticity; Fluid shear stress; Mechanoresponsive; Myosin II; YAP/TAZ

DOI:  https://doi.org/10.1242/jcs.264293
Sci Immunol. 2025 Sep 26. 10(111): eadx1582

Design of a potent interleukin-21 mimic for cancer immunotherapy.

Jung-Ho Chun, Birkley S Lim, Suyasha Roy, Michael J Walsh, Gita C Abhiraman, Kevin Zhangxu, Tavus Atajanova, Or-Yam Revach, Elisa C Clark, Peng Li, Claire A Palin, Asheema Khanna, Samantha Tower, Rakeeb Kureshi, Megan T Hoffman, Tatyana Sharova, Aleigha Lawless, Sonia Cohen, Genevieve M Boland, Tina Nguyen, Frank Peprah, Julissa G Tello, Samantha Y Liu, Chan Johng Kim, Hojeong Shin, Alfredo Quijano-Rubio, Kevin M Jude, Stacey Gerben, Analisa Murray, Piper Heine, Michelle DeWitt, Umut Y Ulge, Lauren Carter, Neil P King, Daniel-Adriano Silva, Hao Yuan Kueh, Vandana Kalia, Surojit Sarkar, Russell W Jenkins, K Christopher Garcia, Warren J Leonard, Michael Dougan, Stephanie K Dougan, David Baker.

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a range of affinities for tumor antigens while suppressing regulatory T cells. Computational protein design has enabled the precise tailoring of proteins to meet specific needs. Here, we report a de novo designed IL-21 mimic, 21h10, with high stability and signaling potency in humans and mice. In murine and ex vivo human organotypic tumor models, 21h10 showed robust antitumor activity, with more prolonged signaling and stronger antitumor activity than native IL-21. 21h10 induced pancreatitis that could be mitigated by TNF blockade without compromising antitumor efficacy. Although antidrug antibodies to 21h10 formed, they were not neutralizing. 21h10 induced highly cytotoxic T cells with a range of affinities, robustly expanding intratumoral low-affinity cytotoxic T cells and driving high expression of IFN-γ and granzyme B compared with native IL-21, while increasing the frequency of IFN-γ+ T helper 1 cells and reducing regulatory T cells. The full human-mouse cross-reactivity, high stability and potency, and low-affinity antitumor responses support the translational potential of 21h10.

DOI: https://doi.org/10.1126/sciimmunol.adx1582
Trends Cell Biol. 2025 Sep 19. pii: S0962-8924(25)00198-9. [Epub ahead of print]

Organelle-specific signaling of cGAS-STING.

Shengduo Liu, Ailian Wang, Chen Chen, Pinglong Xu.

  Innate immune sensing through cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) surveils cytosolic DNA from invading pathogens or damaged organelles and initiates a spectrum of immune responses. It is well established that upon 2'3'-cyclic GMP-AMP (cGAMP) binding, STING exits the endoplasmic reticulum (ER), traverses the Golgi to trigger interferon programs, and finally reaches lysosomes for signal resolution through degradation, revealing a tightly choreographed itinerary for cytokine-driven immunity. However, emerging studies reveal additional layers of spatiotemporal complexity: ER-resident STING tunes in messenger RNA translation and Ca2+ efflux, Golgi-localized STING functions as a proton channel that initiates H+-dependent autophagy and transcription factor EB-directed programs for organelle homeostasis, and various mechanisms for metabolic remodeling and cell fate determination. This review synthesizes emerging organelle-specific mechanisms of cGAS-STING, delineates their roles in physiology and disease, and discusses how an organelle-centric perspective may inform selective, context-sensitive immunotherapies.

Keywords:  cGAS–STING; cellular function; innate immunity; organelle; signaling mechanism; trafficking

DOI:  https://doi.org/10.1016/j.tcb.2025.08.007
Nat Commun. 2025 Sep 26. 16(1): 8499

Comparison of imaging based single-cell resolution spatial transcriptomics profiling platforms using formalin-fixed paraffin-embedded tumor samples.

RTI Team

Imaging-based spatial transcriptomics (ST) is evolving as a pivotal technology in studying tumor biology and associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. We use serial 5 μm sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma samples in tissue microarrays to compare the performance of the ST platforms (CosMx, MERFISH, and Xenium (uni/multi-modal)) in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx, and hematoxylin and eosin staining data. In addition to an objective assessment of automatic cell segmentation and phenotyping, we perform a manual phenotyping evaluation to assess pathologically meaningful comparisons between ST platforms. Here, we show the intricate differences between the ST platforms, reveal the importance of parameters such as probe design in determining the data quality, and suggest reliable workflows for accurate spatial profiling and molecular discovery.

DOI: https://doi.org/10.1038/s41467-025-63414-1
Cancer Cell. 2025 Sep 25. pii: S1535-6108(25)00393-9. [Epub ahead of print]

Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches.

Xiongfeng Chen, Zhuan Zhou, Luyu Xie, Kailiang Qiao, Yiyue Jia, Shunheng Liu, Zeynep Yazgan, Francesca Rossi, Yang Liu, Bo Zhang, Patricio M Polanco, Herbert J Zeh, Alex C Kim, Huocong Huang.

  Recent studies identify a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain poorly understood. To gain a comprehensive understanding of the origin and function of apCAFs, we construct a fibroblast molecular atlas across 15 types of tissues and solid tumors. Our integration study unexpectedly reveals two distinct apCAF populations present in most cancer types: one associated with mesothelial-like cells and the other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF populations. We find that mesothelial-like apCAFs are located near cancer cells, while fibrocyte-like apCAFs are associated with lymphocyte-enriched niches. Additionally, we discovered that both apCAF populations can up-regulate secreted phosphoprotein 1 (SPP1), which facilitates primary tumor formation, peritoneal metastasis, and therapy resistance. Taken together, this study offers an unprecedented resolution in analyzing apCAFs and their spatial niches.

Keywords:  cancer-associated fibroblast; fibrocyte; mesothelial cell; pancreatic cancer; peritoneal metastasis

DOI:  https://doi.org/10.1016/j.ccell.2025.09.001
Cold Spring Harb Perspect Biol. 2025 Sep 22. pii: a041755. [Epub ahead of print]

A Mechanometabolism Toolbox for Studying Cell Migration.

Katherine M Young, Santiago Lopez, Keefer Boone, Mehmet Acikel, Xavi Gallart, Cynthia Reinhart-King.

Cell migration is greatly affected by both the physical properties of the motile cell itself and the environment through which the cell is moving. In addition to studying cellular and extracellular mechanical properties in the context of cell migration, there is a growing interest in understanding the intersection between migration, mechanics, and metabolism. In this work, we discuss the many techniques and approaches researchers are currently using to study cellular mechanics, extracellular mechanics, and metabolism in the context of cell migration. Our goal is to bring exposure to new approaches in the fields of mechanobiology and mechanometabolism and highlight the importance of studying cell migration through a mechanical lens.

DOI: https://doi.org/10.1101/cshperspect.a041755
Sci Transl Med. 2025 Sep 24. 17(817): eads5769

Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice.

Fangyuan Gao, Emily Tom, Cezary Rydz, William Cho, Alexander V Kolesnikov, Yutong Sha, Anastasios Papadam, Samantha Jafari, Andrew Joseph, Ava Ahanchi, Nika Balalaei Someh Saraei, David C Lyon, Andrzej Foik, Qing Nie, Felix Grassmann, Vladimir J Kefalov, Dorota Skowronska-Krawczyk.

The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), primarily localized in cell membranes, where they govern membrane biophysical properties. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, which is associated with normal age-related reductions in contrast sensitivity, diminished photoreceptor function and delayed rod-mediated dark adaptation recovery, and pathological age-related macular degeneration (AMD). ELOVL2 (elongation of very long chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs. The methylation status of the ELOVL2 promoter is currently one of the best predictors of chronological age. Here, we show that lower VLC-PUFA abundance in the aged mouse retina is accompanied by a reduction in visual function. Similarly, mice lacking ELOVL2-specific enzymatic activity (Elovl2C234W) demonstrate reduced contrast sensitivity and slower rod-mediated dark adaptation. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function for up to 4 weeks and reduced accumulation of APOE- and C3d-positive sub-RPE deposits. The gene expression pattern observed in supplemented retinas exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature resembling younger retinas. Last, human genetic data from the IAMDGC and UK Biobank linked two variants in the ELOVL2 locus with the onset of intermediate AMD, underlining the translational importance of our findings. Our work highlights VLC-PUFA supplementation as a potential therapeutic opportunity and defines ELOVL2 as a promising target for interventions to prevent age-related vision loss.

DOI: https://doi.org/10.1126/scitranslmed.ads5769
Database (Oxford). 2025 Jan 18. pii: baaf046. [Epub ahead of print]2025

ScLineageAtlas: a comprehensive single-cell genomics database for characterizing cellular clones in cancer.

Jinyang Liu, Rui Hou, Junlin Xu, Tingting Hui, Haotian Tian, Yankun Liu, Meijun Zhang, Geng Tian, Jialiang Yang.

Accurate identification of clonal relationships between cell populations is crucial for investigating cellular differentiation trajectories and gaining insights into the underlying mechanisms of cancer initiation and development. The Single Cell Lineage Atlas (ScLineageAtlas; https://www.scladb.geneis.org.cn) is a comprehensive single-cell genomics database that characterizes cellular clones across various cancer types. The database currently includes 24 processed single-cell RNA sequencing datasets spanning 13 different cancer types. ScLineageAtlas leverages advanced computational methods to identify cellular clones, providing researchers with a detailed understanding of clone relationships and evolutionary dynamics. Additionally, the database offers comprehensive metadata for each sample, enabling researchers to explore contextual information and sample characteristics. The spatial visualization of cell clones presented in the ScLineageAtlas provides a valuable tool for enhancing our understanding of the genetic heterogeneity within the tumour microenvironment. Through the analysis of biological differences between these diverse cell populations, researchers can explore key genes and signalling pathways associated with cancer initiation, development, and therapeutic efficacy. In summary, the ScLineageAtlas serves as a user-friendly platform for data operations on cellular clones, facilitating the understanding of tumour heterogeneity, differentiation trajectories, and evolution. It thus contributes significantly to cancer research and clinical practice.

DOI: https://doi.org/10.1093/database/baaf046