bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–03–30
29 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins.
  2. The Importance of Bilayer Asymmetry in Biological Membranes: Insights from Model Membranes.
  3. Ferroptosis spreads to neighboring cells via plasma membrane contacts.
  4. Oxidation of retromer complex controls mitochondrial translation.
  5. Excess surface area of the nuclear lamina enables unhindered cell migration through constrictions.
  6. The activation of INF2 by Piezo1/Ca2+ is required for mesenchymal-to-amoeboid transition in confined environments.
  7. How Early Can Pancreatic Tumors Be Detected Using NMR-Based Urine Metabolic Profiling? Identification of Early-Stage Biomarkers of Tumor Initiation and Progression in an Orthotopic Xenograft Mouse Model of Pancreatic Cancer.
  8. Tackling the next decade of cancer research.
  9. Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition.
  10. Chemiosmotic ATP synthesis by minimal protocells.
  11. Monitoring Autophagy in Human Aging: Key Cell Models and Insights.
  12. Pre-cachectic changes in amino acid homeostasis precede activation of eIF2α signaling in the liver at the onset of C26 cancer-induced cachexia.
  13. Assessing cancer therapeutic efficacy in vivo using [2H7]glucose deuterium metabolic imaging.
  14. Cell compression - relevance, mechanotransduction mechanisms and tools.
  15. Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
  16. HDL Cholesterol Levels and Pancreatic Cancer Risk: Protective Effects Revealed.
  17. Membranes, where lipids and protein meet.
  18. How Does an Anti-Cancer Peptide Passively Permeate the Plasma Membrane of a Cancer Cell and Not a Normal Cell?
  19. The future of cancer research: invest now.
  20. MuPETFlow: multiple ploidy estimation tool from flow cytometry data.
  21. OPRLM: A Web Tool and a Database for Positioning and Simulations of Proteins in Realistic Lipid Membranes.
  22. Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
  23. Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
  24. Microphase separation produces interfacial environment within diblock biomolecular condensates.
  25. Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states.
  26. Fast segmentation and multiplexing imaging of organelles in live cells.
  27. DARLIN mouse for in vivo lineage tracing at high efficiency and clonal diversity.
  28. Cryo-EM structures of a protein pore reveal a cluster of cholesterol molecules and diverse roles of membrane lipids.
  29. Endothelial-like cancer-associated fibroblasts facilitate pancreatic cancer metastasis via vasculogenic mimicry and paracrine signalling.
  1. Science. 2025 Mar 28. 387(6741): eadq8331
    Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins.
    Aakriti Jain, Isaac Heremans, Gilles Rademaker, Tyler C Detomasi, Peter Rohweder, Dashiell Anderson, Justin Zhang, Grace A Hernandez, Suprit Gupta, Teresa von Linde, Mike Lange, Martina Spacci, Jiayi Luo, Y Rose Citron, James A Olzmann, David W Dawson, Charles S Craik, Guido Bommer, Rushika M Perera, Roberto Zoncu.
      Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain-containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.
    DOI:  https://doi.org/10.1126/science.adq8331
  2. Membranes (Basel). 2025 Mar 03. pii: 79. [Epub ahead of print]15(3):
    The Importance of Bilayer Asymmetry in Biological Membranes: Insights from Model Membranes.
    Igor S Oliveira, Guilherme X Pinheiro, Maria Luana B Sa, Pedro Henrique L O Gurgel, Samuel U Pizzol, Rosangela Itri, Vera B Henriques, Thais A Enoki.
      This mini-review intends to highlight the importance of bilayer asymmetry. Biological membranes are complex structures that are a physical barrier separating the external environment from the cellular content. This complex bilayer comprises an extensive lipid repertory, suggesting that the different lipid structures might play a role in the membrane. Interestingly, this vast repertory of lipids is asymmetrically distributed between leaflets that form the lipid bilayer. Here, we discuss the properties of the plasma membrane from the perspective of experimental model membranes, consisting of simplified and controlled in vitro systems. We summarize some crucial features of the exoplasmic (outer) and cytoplasmic (inner) leaflets observed through investigations using symmetric and asymmetric membranes. Symmetric model membranes for the exoplasmic leaflet have a unique lipid composition that might form a coexistence of phases, namely the liquid disordered and liquid order phases. These phase domains may appear in different sizes and shapes depending on lipid composition and lipid-lipid interactions. In contrast, symmetric model membranes for the cytoplasmic leaflet form a fluid phase. We discuss the outcomes reported in the literature for asymmetric bilayers, which vary according to lipid compositions and, consequently, reflect different intra- and inter-leaflet interactions. Interestingly, the asymmetric bilayer could show induced domains in the inner leaflet, or it could decrease the tendency of the outer leaflet to phase separation. If cells regulate the lipid composition of the plasma membrane, they can adjust the existence and sizes of the domains by tuning the lipid composition.
    Keywords:  asymmetric membranes; lipid bilayer; liquid ordered and liquid disordered phases; partition coefficient
    DOI:  https://doi.org/10.3390/membranes15030079
  3. Nat Commun. 2025 Mar 26. 16(1): 2951
    Ferroptosis spreads to neighboring cells via plasma membrane contacts.
    Bernhard F Roeck, Sara Lotfipour Nasudivar, Michael R H Vorndran, Lena Schueller, F Isil Yapici, Matthias Rübsam, Silvia von Karstedt, Carien M Niessen, Ana J Garcia-Saez.
      Ferroptosis is a lytic, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and associated with necrosis spread in diseased tissues through unknown mechanisms. Using a novel optogenetic system for light-driven ferroptosis induction via degradation of the anti-ferroptotic protein GPX4, we show that lipid peroxidation and ferroptotic death can spread to neighboring cells through their closely adjacent plasma membranes. Ferroptosis propagation is dependent on cell distance and completely abolished by disruption of α-catenin-dependent intercellular contacts or by chelation of extracellular iron. Remarkably, bridging cells with a lipid bilayer or increasing contacts between neighboring cells enhances ferroptosis spread. Reconstitution of iron-dependent spread of lipid peroxidation between pure lipid, contacting liposomes provides evidence for the physicochemical mechanism involved. Our findings support a model in which iron-dependent lipid peroxidation propagates across proximal plasma membranes of neighboring cells, thereby promoting the transmission of ferroptotic cell death with consequences for pathological tissue necrosis spread.
    DOI:  https://doi.org/10.1038/s41467-025-58175-w
  4. Nature. 2025 Mar 26.
    Oxidation of retromer complex controls mitochondrial translation.
    Junbing Zhang, Md Yousuf Ali, Harrison Byron Chong, Pei-Chieh Tien, James Woods, Carolina Noble, Tristan Vornbäumen, Zehra Ordulu, Anthony P Possemato, Stefan Harry, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, MinGyu Choi, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Natalya N Pavlova, Michael Lawrence, Justin F Gainor, Sean A Beausoleil, Nabeel Bardeesy, Raul Mostoslavsky, David Pépin, Christopher J Ott, Brian Liau, Liron Bar-Peled.
      Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.
    DOI:  https://doi.org/10.1038/s41586-025-08756-y
  5. Sci Adv. 2025 Mar 28. 11(13): eads6573
    Excess surface area of the nuclear lamina enables unhindered cell migration through constrictions.
    Brendan McKee, Samere Abolghasemzade, Ting-Ching Wang, Kajol Harsh, Simran Kaur, Ryan Blanchard, Krishna Belraj Menon, Mohammad Mohajeri, Richard B Dickinson, Tanmay P Lele.
      Cell migration through narrow spaces is essential in wound healing and metastatic spread of cancer. Cells must deform the large nucleus to fit through constricting channels. To understand the role of the nuclear lamina in limiting cell migration through constrictions, we imaged it in cells migrating through periodic constricting channels in a microdevice. The lamina underwent cycles of wrinkling and smoothing as the nucleus changed from an irregular, rounded shape in the wide channel regions between constrictions to a smooth, hourglass shape as the nucleus passed through the center of a constriction. The laminar surface area of nuclei within constrictions was measured to be at or above the computationally predicted threshold area for the nuclear volume. The channels excluded control nuclei that had insufficient excess surface area, but not nuclei lacking lamin A/C. Thus, the excess surface area of the nuclear lamina enables cell migration through constricting channels.
    DOI:  https://doi.org/10.1126/sciadv.ads6573
  6. Curr Biol. 2025 Mar 16. pii: S0960-9822(25)00280-5. [Epub ahead of print]
    The activation of INF2 by Piezo1/Ca2+ is required for mesenchymal-to-amoeboid transition in confined environments.
    Neelakshi Kar, Alexa P Caruso, Nicos Prokopiou, Alleah Abrenica, Jeremy S Logue.
      To invade tissues, cells may undergo a mesenchymal-to-amoeboid transition (MAT). However, the mechanisms regulating this transition are poorly defined. In melanoma cells, we demonstrate that intracellular [Ca2+] increases with the degree of confinement in a Piezo1-dependent fashion. Moreover, Piezo1/Ca2+ is found to drive amoeboid and not mesenchymal migration in confined environments. Consistent with a model in which Piezo1 senses tension at the plasma membrane, the percentage of cells using amoeboid migration is further increased in undulating microchannels. Surprisingly, amoeboid migration was not promoted by myosin light-chain kinase (MLCK), which is sensitive to intracellular [Ca2+]. Instead, we report that Piezo1/Ca2+ activates inverted formin-2 (INF2) to induce widespread actin cytoskeletal remodeling. Strikingly, the activation of INF2 promotes de-adhesion, which in turn facilitates migration across micropatterned surfaces. Thus, we reveal a novel Piezo1/Ca2+/INF2 signaling cascade that regulates MAT, enabling cancer cells to adapt their migration mode in response to varying mechanochemical environments.
    Keywords:  INF2; Piezo1; ROCK2; amoeboid; bleb; cancer; cell migration; mechanotransduction; metastasis; microenvironment
    DOI:  https://doi.org/10.1016/j.cub.2025.02.066
  7. Metabolites. 2025 Feb 20. pii: 142. [Epub ahead of print]15(3):
    How Early Can Pancreatic Tumors Be Detected Using NMR-Based Urine Metabolic Profiling? Identification of Early-Stage Biomarkers of Tumor Initiation and Progression in an Orthotopic Xenograft Mouse Model of Pancreatic Cancer.
    Tafadzwa Chihanga, Shenyuan Xu, Hannah N Fultz, Jenna D Nicholson, Mark D Brombacher, Kayla Hawkins, Dan R Fay, Maria M Steil, Shuisong Ni, Michael A Kennedy.
      Background: Pancreatic cancer is the most lethal of all human cancers. The disease has no obvious symptoms in its early stages and in the majority of cases, the cancer goes undetected until it has advanced to the point that surgery is no longer a viable option or until it has metastasized to other organs. The absence of reliable and sensitive biomarkers for the early detection of pancreatic cancer contributes to the poor ability to detect the disease before it progresses to an untreatable stage. Objectives: Here, an orthotopic xenograft mouse model of pancreatic cancer was investigated to determine if urinary metabolic biomarkers could be identified and used to detect the early formation of pancreatic tumors. Methods: The orthotopic xenograft mouse model of pancreatic cancer was established by injecting human MiaPaCa-2 cells, derived from a male patient aged 65 years with pancreatic adenocarcinoma, into the pancreata of severe combined immunodeficient mice. Orthotopic pancreatic tumors, allowed to grow for eight weeks, were successfully established in the pancreata in 15 out of 20 mice. At the time of sacrifice, tumors were excised and histologically analyzed and the masses and volumes recorded. Urine samples were collected prior to injection, at one-week post injection, and every two weeks afterwards for eight weeks. Results: NMR-based metabolic profiling of the urine samples indicated that 31 metabolites changed significantly over the course of tumor initiation and growth. Longitudinal metabolic profiling analysis indicated an initial increase in activity of the metabolic pathways involved in energy production and/or cell synthesis by cancer cells as required to support tumor growth that was followed by a diminished difference between control and orthotopic mice associated with tumor senescence as the tumors reached 7-8 weeks post injection. Conclusions: The results indicate that NMR-based urinary metabolic profiling may be able to detect the earliest stages of pancreatic tumor initiation and growth, highlighting the potential for translation to human clinical studies.
    Keywords:  MiaPaCa-2; NMR; PDAC; metabolomics; metabonomics; mouse model; orthotopic; pancreatic cancer; urine; xenograft
    DOI:  https://doi.org/10.3390/metabo15030142
  8. Trends Cancer. 2025 Mar 24. pii: S2405-8033(25)00072-X. [Epub ahead of print]
    Tackling the next decade of cancer research.
    Raza Ali, Brittany Jenkins, Wouter Karthaus, Jana Lipkova, Sandra Misale, Jens Puschhof, Melody Smith, Santosha Vardhana, Xin Zhou.
      
    DOI:  https://doi.org/10.1016/j.trecan.2025.03.004
  9. J Clin Invest. 2025 Mar 25. pii: e181609. [Epub ahead of print]
    Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition.
    Yuyi Wang, Hidetaka Ohnuki, Andy D Tran, Dunrui Wang, Taekyu Ha, Jing-Xin Feng, Minji Sim, Raymond Barnhill, Claire Lugassy, Michael R Sargen, Emanuel Salazar-Cavazos, Michael Kruhlak, Giovanna Tosato.
      Allosteric inhibitors of the tyrosine phosphatase SHP2 hold therapeutic promise in cancers with overactive RAS/ERK signaling but "adaptive resistance" to SHP2 inhibitors may limit benefits. Here, we utilized tumor cells that proliferate similarly with or without endogenous SHP2 to explore means to overcome this growth-independence from SHP2. We found that SHP2 depletion profoundly alters output of vascular regulators, cytokines, chemokines, and other factors from SHP2 growth-resistant cancer cells. Tumors derived from inoculation of SHP2-depleted, but SHP2 growth-independent, mouse melanoma and colon carcinoma cell lines display a typically subverted architecture where proliferative tumor cells cluster in distinct "vascular islands" centered by remodeled vessels, each limited by surrounding hypoxic and dead tumor tissue, where inflammatory blood cells are limited. Although vascular islands generally reflect protected sanctuaries for tumor cells, we found that vascular island-resident, highly proliferative, SHP2-depleted tumor cells acquire an increased sensitivity to blocking MEK/ERK signaling resulting in reduced tumor growth. Our results show that response to targeted therapies in resistant tumor cells is controlled by tumor cell-induced vascular changes and tumor architectural reorganization providing a compelling approach to eliciting tumor response by exploiting tumor and endothelial-dependent biochemical changes.
    Keywords:  Angiogenesis; Cancer; Chemokines; Endothelial cells; Oncology
    DOI:  https://doi.org/10.1172/JCI181609
  10. Cell Rep Phys Sci. 2025 Mar 19. 6(3): 102461
    Chemiosmotic ATP synthesis by minimal protocells.
    Fanchen Yu, Jinbo Fei, Yi Jia, Tonghui Wang, William F Martin, Junbai Li.
      Energy conservation is crucial to life's origin and evolution. The common ancestor of all cells used ATP synthase to convert proton gradients into ATP. However, pumps generating proton gradients and lipids maintaining proton gradients are not universally conserved across all lineages. A solution to this paradox is that ancestral ATP synthase could harness naturally formed geochemical ion gradients with simpler environmentally provided precursors preceding both proton pumps and biogenic membranes. This runs counter to traditional views that phospholipid bilayers are required to maintain proton gradients. Here, we show that fatty acid membranes can maintain sufficient proton gradients to synthesize ATP by ATP synthase under the steep pH and temperature gradients observed in hydrothermal vent systems. These findings shed substantial light on early membrane bioenergetics, uncovering a functional intermediate in the evolution of chemiosmotic ATP synthesis during protocellular stages postdating the ATP synthase's origin but preceding the advent of enzymatically synthesized cell membranes.
    Keywords:  ATP synthesis; gradients; hydrothermal vent chemistry; membrane bioenergetics; nanoarchitectonics; origin of life; protocell; supramolecular chemistry
    DOI:  https://doi.org/10.1016/j.xcrp.2025.102461
  11. Front Biosci (Landmark Ed). 2025 Mar 20. 30(3): 27091
    Monitoring Autophagy in Human Aging: Key Cell Models and Insights.
    Tatiana M Moreno, Jose L Nieto-Torres, Caroline Kumsta.
      Autophagy, a key cellular degradation and recycling pathway, is critical for maintaining cellular homeostasis and responding to metabolic and environmental stress. Evidence for age-related autophagic dysfunction and its implications in chronic age-related diseases including neurodegeneration is accumulating. However, as a complex, multi-step process, autophagy can be challenging to measure, particularly in humans and human aging- and disease-relevant models. This review describes the links between macroautophagy, aging, and chronic age-related diseases. We present three novel human cell models, peripheral blood mononuclear cells (PBMCs), primary dermal fibroblasts (PDFs), and induced neurons (iNs), which serve as essential tools for studying autophagy flux and assessing its potential as a biomarker for aging. Unlike traditional models, these cell models retain age- and disease-associated molecular signatures, enhancing their relevance for human studies. The development of robust tools and methodologies for measuring autophagy flux in human cell models holds promise for advancing our understanding of autophagy's role in aging and age-related diseases, ultimately facilitating the discovery of therapies to enhance health outcomes.
    Keywords:  aging; autophagy; biomarkers; chronic age-related diseases; human cell models; induced neurons (iNs); peripheral blood mononuclear cells (PBMCs); primary dermal fibroblasts (PDFs)
    DOI:  https://doi.org/10.31083/FBL27091
  12. iScience. 2025 Mar 21. 28(3): 112030
    Pre-cachectic changes in amino acid homeostasis precede activation of eIF2α signaling in the liver at the onset of C26 cancer-induced cachexia.
    Ghita Chaouki, Laurent Parry, Cyrielle Vituret, Céline Jousse, Martin Leremboure, Céline Bourgne, Laurent Mosoni, Yoann Delorme, Mehdi Djelloul-Mazouz, Julien Hermet, Julien Averous, Alain Bruhat, Lydie Combaret, Daniel Taillandier, Isabelle Papet, Laure B Bindels, Pierre Fafournoux, Anne-Catherine Maurin.
      The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased albumin expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112030
  13. Sci Adv. 2025 Mar 28. 11(13): eadr0568
    Assessing cancer therapeutic efficacy in vivo using [2H7]glucose deuterium metabolic imaging.
    Mario C Chang, Vinay R Malut, Rohit Mahar, Anna Rushin, Marc A McLeod, Geraldine L Pierre, Indu R Malut, Stephen J Staklinski, Max E Glanz, Mukundan Ragavan, Gaurav Sharma, Manoj Madheswaran, Arshee Badar, Aparna D Rao, Brian K Law, Michael S Kilberg, James H P Collins, Vikram D Kodibagkar, James A Bankson, Ralph J DeBerardinis, Matthew E Merritt.
      Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention. Deuterium magnetic resonance imaging (DMRI) with [6,6-2H2]glucose is nonradioactive, achieves tumor metabolic contrast, but can be improved by enriched contrast from deuterated water (HDO) based imaging. Here, we developed a DMRI protocol employing [2H7]glucose. Imaging 2H-signal and measuring HDO production in tumor-bearing mice detected differential glucose utilization across baseline tumors, tumors treated with vehicle control or anti-glycolytic BRAFi and MEKi therapy, and contralateral healthy tissue. Control tumors generated the most 2H-signal and HDO. To our knowledge this is the first application of DMRI with [2H7]glucose for tumoral treatment monitoring. This approach demonstrates HDO as a marker of tumor glucose utilization and suggests translational capability in humans due to its safety, noninvasiveness, and suitability for serial monitoring.
    DOI:  https://doi.org/10.1126/sciadv.adr0568
  14. J Cell Sci. 2025 Mar 15. pii: jcs263704. [Epub ahead of print]138(6):
    Cell compression - relevance, mechanotransduction mechanisms and tools.
    Laura M Faure, Valeria Venturini, Pere Roca-Cusachs.
      From border cell migration during Drosophila embryogenesis to solid stresses inside tumors, cells are often compressed during physiological and pathological processes, triggering major cell responses. Cell compression can be observed in vivo but also controlled in vitro through tools such as micro-channels or planar confinement assays. Such tools have recently become commercially available, allowing a broad research community to tackle the role of cell compression in a variety of contexts. This has led to the discovery of conserved compression-triggered migration modes, cell fate determinants and mechanosensitive pathways, among others. In this Review, we will first address the different ways in which cells can be compressed and their biological contexts. Then, we will discuss the distinct mechanosensing and mechanotransducing pathways that cells activate in response to compression. Finally, we will describe the different in vitro systems that have been engineered to compress cells.
    Keywords:   In vitro systems; Cytoskeleton; Mechanobiology; Mechanosensation; Mechanotransduction; Membrane
    DOI:  https://doi.org/10.1242/jcs.263704
  15. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2426929122
    Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
    Ayse Z Sahan, Mingyuan Chen, Qi Su, Qingrong Li, Dong Wang, Jin Zhang.
      3-Phosphoinositides (3-PIs), phosphatidylinositol (3,4) bisphosphate [PI(3,4)P2] and phosphatidylinositol (3,4,5) trisphosphate (PIP3), are important lipid second messengers in the Phosphoinositide 3-Kinase (PI3K)/Akt signaling pathway, which is crucial to cell growth and frequently dysregulated in cancer. Emerging evidence suggests these lipid second messengers may be present in membranes beyond the plasma membrane, yet their spatial regulation within other membrane compartments is not well understood. To dissect the spatial regulation of specific 3-PI species, we developed genetically encodable biosensors with selectivity for PIP3 or PI(3,4)P2. Using these biosensors, we showed that PIP3 significantly accumulated at the lysosome upon growth factor stimulation, in contrast to the conventional view that PIP3 is exclusively present in the plasma membrane. Furthermore, we showed that lysosomal PIP3 originates from the plasma membrane and relies on dynamin-dependent endocytosis for lipid internalization. Thus, PIP3 can exploit dynamic trafficking pathways to access subcellular compartments and regulate signaling in a spatially selective manner.
    Keywords:  3-phosphoinositide; cellular signaling; fluorescent biosensor; lysosome; spatiotemporal regulation
    DOI:  https://doi.org/10.1073/pnas.2426929122
  16. Curr Cancer Drug Targets. 2025 Mar 25.
    HDL Cholesterol Levels and Pancreatic Cancer Risk: Protective Effects Revealed.
    Yiming Shao, Rui Hao, Si Si Lin, Ba-Fang Ma, Jun-Nan Ye, Mayila Maimaiti, Yasen Maimaitiyiming.
       BACKGROUND: The causal relationship between lipoprotein traits and the risk of pancre-atic cancer (PC) remains unclear. In this study, we employed a two-sample Mendelian randomiza-tion (MR) approach to explore the untangled relationship between lipoprotein traits and PC.
    METHODS: Univariable MR analyses were used to determine the causal connection between lipo-protein traits and PC. Instrumental variables corresponding to lipoprotein traits were taken from the Global Lipids Genetics Consortium (GLGC) (n = 188,578). The outcome dataset was created from PC summary-level data (n case = 1896, n control = 1939) from a genome-wide association study of European ancestry. Causal effects were evaluated using the inverse variance weighted (IVW) method. For sensitivity analysis, both the weighted median (WM) and MR-Egger methods, among others, were utilized. We also conducted multivariable MR analyses to examine potential confounders.
    RESULTS: In univariable MR, IVW methods supported evidence that HDL cholesterol (OR = 0.463, 95% CI: 0.313-0.685; P = 1.10×10-4) was linked with a decreased risk of PC. These findings were consistent across other MR methods, including MR-Egger (OR = 0.340, 95% CI: 0.182-0.638; P = 1.30×10-3) and WM (OR = 0.367, 95% CI: 0.195-0.692; P = 1.90×10-3). Our results displayed no significant heterogeneity or horizontal pleiotropy. Furthermore, these associations persisted in the multivariable MR analysis after adjusting for confounding factors such as smok-ing, alcohol consumption, and body mass index (BMI).
    CONCLUSIONS: Our comprehensive MR analyses consistently demonstrate a protective association between higher HDL cholesterol levels and decreased PC risk, even after adjustments for key life-style factors and BMI.
    Keywords:  HDL cholesterol; Mendelian Randomization; Pancreatic cancer; biomarkers; cancer risk; causal relationship.; lipid metabolism; lipoprotein traits
    DOI:  https://doi.org/10.2174/0115680096334509241218141459
  17. Chem Phys Lipids. 2025 Mar 22. pii: S0009-3084(25)00022-2. [Epub ahead of print]268 105486
    Membranes, where lipids and protein meet.
    Diego de Mendoza.
      Membrane proteins have central roles in a vast number of vital cellular processes. A common structural feature of most membrane proteins is the presence of one or more hydrophobic alpha-helices that interact with the lipid bilayer. Because of the interaction with the surrounding lipids, the organization of these helices will be sensitive to lipid properties like fluidity and hydrophobic thickness. The helices may adapt to the lipids in different ways, which in turn can influence the structure and function of the intact membrane protein. In this review article, I will focus on how the lipid environment governs the signaling state of a transmembrane protein and in how the lipid bilayer influences the catalytic and substrate channeling role of a peripheral protein.
    Keywords:  Lipid bilayer; Lipid properties; Membrane proteins; Phospholipids
    DOI:  https://doi.org/10.1016/j.chemphyslip.2025.105486
  18. J Phys Chem B. 2025 Mar 24.
    How Does an Anti-Cancer Peptide Passively Permeate the Plasma Membrane of a Cancer Cell and Not a Normal Cell?
    Alfredo E Cardenas, Ehud Neumann, Yang Sung Sohn, Taylor Hays, Rachel Nechushtai, Lauren J Webb, Ron Elber.
      Passive and targeted delivery of peptides to cells and organelles is a fundamental biophysical process controlled by membranes surrounding biological compartments. Embedded proteins, phospholipid composition, and solution conditions contribute to targeted transport. An anticancer peptide, NAF-144-67, permeates to cancer cells but not to normal cells. The mechanism of this selectivity is of significant interest. However, the complexity of biomembranes makes pinpointing passive targeting mechanisms difficult. To dissect contributions to selective transport by membrane components, we constructed simplified phospholipid vesicles as plasma membrane (PM) models of cancer and normal cells and investigated NAF-144-67 permeation computationally and experimentally. We use atomically detailed simulations with enhanced sampling techniques to study kinetics and thermodynamics of the interaction. Experimentally, we study the interaction of the peptide with large and giant unilamellar vesicles. The large vesicles were investigated with fluorescence spectroscopy and the giant vesicles with confocal microscopy. Peptide permeation across a model of cancer PM is more efficient than permeation across a PM model of normal cells. The investigations agree on the mechanism of selectivity, which consists of three steps: (i) early electrostatic attraction of the peptide to the negatively charged membrane, (ii) the penetration of the peptide hydrophobic N-terminal segment into the lipid bilayer, and (iii) exploiting short-range electrostatic forces to create a defect in the membrane and complete the permeation process. The first step is kinetically less efficient in a normal membrane with fewer negatively charged phospholipids. The model of a normal membrane is less receptive to defect creation in the third step.
    DOI:  https://doi.org/10.1021/acs.jpcb.5c00680
  19. Trends Cancer. 2025 Mar 24. pii: S2405-8033(25)00075-5. [Epub ahead of print]
    The future of cancer research: invest now.
    Danielle T Loughlin.
      
    DOI:  https://doi.org/10.1016/j.trecan.2025.03.007
  20. BMC Genomics. 2025 Mar 26. 26(1): 301
    MuPETFlow: multiple ploidy estimation tool from flow cytometry data.
    C Gómez-Muñoz, G Fischer.
       BACKGROUND: Ploidy, representing the number of homologous chromosome sets, can be estimated from flow cytometry data acquired on cells stained with a fluorescent DNA dye. This estimation relies on a combination of tools that often require scripting, individual sample curation, and additional analyses.
    RESULTS: To automate the ploidy estimation for multiple flow cytometry files, we developed MuPETFlow-a Shiny graphical user interface tool. MuPETFlow allows users to visualize cell fluorescence histograms, detect the peaks corresponding to the different cell cycle phases, perform a linear regression using standards, make ploidy or genome size predictions, and export results as figures and table files. The tool was benchmarked with known ploidy datasets from yeast and plant species, yielding consistent ploidy results. MuPETFlow's peaks detection and performance were also compared to those of other tools.
    CONCLUSIONS: MuPETFlow stands out as the only tool offering in-app ploidy detection, multiple peak detection, multi-sample visualization, and automation capabilities. These features significantly accelerate the analysis, making it especially valuable for projects involving large datasets.
    Keywords:  Cytometry; Genome; Graphical user interface; Ploidy; Software
    DOI:  https://doi.org/10.1186/s12864-025-11470-8
  21. J Mol Biol. 2025 Jan 27. pii: S0022-2836(25)00032-4. [Epub ahead of print] 168966
    OPRLM: A Web Tool and a Database for Positioning and Simulations of Proteins in Realistic Lipid Membranes.
    Sang-Jun Park, Kyle A Schnitzer, Alexey Kovalenko, Stanislav Cherepanov, L Ponoop Prasad Patro, Zigang Song, Irina D Pogozheva, Andrei L Lomize, Wonpil Im.
      Molecular dynamics (MD) simulations in explicit lipid bilayers enable modeling of protein-lipid interactions essential for membrane protein functions and regulation. The newly developed computational web tool, OPRLM (Orientations of Proteins in Realistic Lipid Membranes), automates the assembly of membrane protein structures with explicit lipids corresponding to 18 biological membrane types with symmetric or asymmetric lipid distributions, as well as 5 types of two-component lipid bilayers with varying cholesterol content. Built upon the CHARMM-GUI toolset and the PPM method, OPRLM simplifies the setup of complex simulation system involving integral and/or peripheral membrane proteins with explicit lipid mixtures and generates all necessary files for subsequent all-atom MD simulations. OPRLM has successfully generated protein-membrane systems for 286 tested protein structures in various biomembranes, including 138 structures containing ligands. The OPRLM database, an advanced successor of the OPM database, includes explicit protein-lipid systems for tested proteins in their native biomembranes. It provides coordinates of integral and peripheral membrane proteins from the Protein Data Bank embedded in planar or curved implicit lipid bilayers. Additionally, it includes the classification of proteins into types, superfamilies, and families, along with the information on intracellular localizations and membrane topology and visualization options. The OPRLM web tool and the database are publicly accessible at https://oprlm.org.
    Keywords:  biomembrane; explicit lipid; lipid bilayer; peripheral membrane protein; transmembrane
    DOI:  https://doi.org/10.1016/j.jmb.2025.168966
  22. J Cell Biol. 2025 May 05. pii: e202405060. [Epub ahead of print]224(5):
    Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
    Yazhen Huo, Xinlu Liu, Chen Lu, Tao Li, Zaili Yang, Fenfen Xu, Si Chen, Kailin Yin, Likun Wang.
      Under endoplasmic reticulum (ER) stress (ERS), cells initiate the unfolded protein response (UPR) to maintain ER homeostasis. Recent studies revealed ERS transmission between cells and tissues, by activating the cell-nonautonomous UPR in cells that do not experience ERS directly. Here, we report that ERS triggers a rapid release of ceramide independent of the UPR, but requiring the acid sphingomyelinase activity. Carried by lipoproteins, ceramide is delivered to receiving cells to induce the UPR and regulate cell functions at multiple aspects, including lipid accumulation, cell death, and cytokine production. Mechanistically, extracellular ceramide stimulates ceramide synthesis at the transcription level in receiving cells, leading to ceramide accumulation in the ER so as to reduce membrane fluidity to disrupt ER calcium homeostasis, thus activating the UPR. Sphingomyelin counterbalanced the effect of ceramide. UPR induction is the frontline response to protect cells from ceramide insult. Our study suggests ceramide-mediated ERS transmission as a universal cell-cell communication model regulating a wide range of physiological events.
    DOI:  https://doi.org/10.1083/jcb.202405060
  23. Nat Metab. 2025 Mar 25.
    Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
    Dylan J Duerre, Julia K Hansen, Steven V John, Annie Jen, Noah D Carrillo, Hoang Bui, Yutong Bao, Matias Fabregat, J Leon Catrow, Li-Yu Chen, Katherine A Overmyer, Evgenia Shishkova, Quentinn Pearce, Mark P Keller, Richard A Anderson, Vincent L Cryns, Alan D Attie, James E Cox, Joshua J Coon, Jing Fan, Andrea Galmozzi.
      The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes. Inhibiting haem biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, owing to a haem-associated metabolon that channels BCAA-derived carbons into haem biosynthesis. Haem synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels than wild-type cells. Although exogenous haem supplementation can restore intracellular haem levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted haem synthesis. Finally, disruption of haem biosynthesis in BAT impairs thermogenic response and, in female but not male mice, hinders the cold-induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose haem biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.
    DOI:  https://doi.org/10.1038/s42255-025-01253-6
  24. Elife. 2025 Mar 26. pii: RP90750. [Epub ahead of print]12
    Microphase separation produces interfacial environment within diblock biomolecular condensates.
    Andrew P Latham, Longchen Zhu, Dina A Sharon, Songtao Ye, Adam P Willard, Xin Zhang, Bin Zhang.
      The phase separation of intrinsically disordered proteins is emerging as an important mechanism for cellular organization. However, efforts to connect protein sequences to the physical properties of condensates, that is, the molecular grammar, are hampered by a lack of effective approaches for probing high-resolution structural details. Using a combination of multiscale simulations and fluorescence lifetime imaging microscopy experiments, we systematically explored a series of systems consisting of diblock elastin-like polypeptides (ELPs). The simulations succeeded in reproducing the variation of condensate stability upon amino acid substitution and revealed different microenvironments within a single condensate, which we verified with environmentally sensitive fluorophores. The interspersion of hydrophilic and hydrophobic residues and a lack of secondary structure formation result in an interfacial environment, which explains both the strong correlation between ELP condensate stability and interfacial hydrophobicity scales, as well as the prevalence of protein-water hydrogen bonds. Our study uncovers new mechanisms for condensate stability and organization that may be broadly applicable.
    Keywords:  biochemistry; biomolecular condensates; chemical biology; hydrophobicity; molecular biophysics; molecular dynamics; multiscale simulations; none; structural biology
    DOI:  https://doi.org/10.7554/eLife.90750
  25. Cell Rep Med. 2025 Mar 22. pii: S2666-3791(25)00115-6. [Epub ahead of print] 102042
    Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states.
    Beckey Trinh, Signe Johanne Rasmussen, Mathilde Ehnhuus Brøgger-Jensen, Christoph Andreas Engelhard, Anton Lund, Ana Rita Tavanez, Alexandra Vassilieva, Susanne Janum, Ulrik Winning Iepsen, Bente Kiens, Kirsten Møller, Bente Klarlund Pedersen, Gerrit Van Hall, Helga Ellingsgaard.
      Interleukin-6 (IL-6) knockout mice and humans treated with IL-6 receptor blockade gain adipose tissue mass. This study investigates whether basal IL-6 activity (resting IL-6 levels) influences fat storage during fasting and postprandial states. Using stable-isotope tracer techniques and IL-6 receptor blockade with tocilizumab, we examine fat kinetics in humans. Blocking basal IL-6 activity reduces fasting whole-body lipolysis, decreases hormone-sensitive lipase (HSL) phosphorylation and fatty acid release in adipose tissue, and impairs postprandial fatty acid uptake in the leg. These results suggest diminished fatty acid uptake and oxidation in skeletal muscle, along with enhanced fatty acid entrapment in adipose tissue, which may account for the increased adiposity in the absence of IL-6 activity. Additionally, IL-6 blockade increases the escape of meal-derived fatty acids into the bloodstream. Whether this affects fatty acid storage and lipotoxicity in other tissues warrants further investigation. This study was registered at ClinicalTrials.gov (NCT04687540).
    Keywords:  fasting; fatty acids; homeostasis; humans; interleukin-6; isotopes; lipolysis; nutrients; obesity; tocilizumab
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102042
  26. Nat Commun. 2025 Mar 21. 16(1): 2769
    Fast segmentation and multiplexing imaging of organelles in live cells.
    Karl Zhanghao, Meiqi Li, Xingye Chen, Wenhui Liu, Tianling Li, Yiming Wang, Fei Su, Zihan Wu, Chunyan Shan, Jiamin Wu, Yan Zhang, Jingyan Fu, Peng Xi, Dayong Jin.
      Studying organelles' interactome at system level requires simultaneous observation of subcellular compartments and tracking their dynamics. Conventional multicolor approaches rely on specific fluorescence labeling, where the number of resolvable colors is far less than the types of organelles. Here, we use a lipid-specific dye to stain all the membrane-associated organelles and spinning-disk microscopes with an extended resolution of ~143 nm for high spatiotemporal acquisition. Due to the chromatic polarity sensitivity, high-resolution ratiometric images well reflect the heterogeneity of organelles. With deep convolutional neuronal networks, we successfully segmented up to 15 subcellular structures using one laser excitation. We further show that transfer learning can predict both 3D and 2D datasets from different microscopes, different cell types, and even complex systems of living tissues. We succeeded in resolving the 3D anatomic structure of live cells at different mitotic phases and tracking the fast dynamic interactions among six intracellular compartments with high robustness.
    DOI:  https://doi.org/10.1038/s41467-025-57877-5
  27. Nat Protoc. 2025 Mar 21.
    DARLIN mouse for in vivo lineage tracing at high efficiency and clonal diversity.
    Li Li, Sarah Bowling, Hongying Lin, Daolong Chen, Shou-Wen Wang, Fernando D Camargo.
      Lineage tracing is a powerful tool to study cell history and cell dynamics during tissue development and homeostasis. An increasingly popular approach for lineage tracing is to generate high-frequent mutations at given genomic loci, which can serve as genetic barcodes to label different cell lineages. However, current lineage tracing mouse models suffer from low barcode diversity and limited single-cell lineage coverage. We recently developed the DARLIN mouse model by incorporating three barcoding arrays within defined genomic loci and combining Cas9 and terminal deoxynucleotidyl transferase (TdT) to improve editing diversity in each barcode array. We estimated that DARLIN generates 1018 distinct lineage barcodes in theory, and enables the recovery of lineage barcodes in over 70% of cells in single-cell assays. In addition, DARLIN can be induced with doxycycline to generate stable lineage barcodes across different tissues at a defined stage. Here we provide a step-by-step protocol on applying the DARLIN system for in vivo lineage tracing, including barcode induction, estimation of induction efficiency, barcode analysis with bulk and single-cell sequencing, and computational analysis. The execution time of this protocol is ~1 week for experimental data collection and ~1 d for running the computational analysis pipeline. To execute this protocol, one should be familiar with sequencing library generation and Linux operation. DARLIN opens the door to study the lineage relationships and the underlying molecular regulations across various tissues at physiological context.
    DOI:  https://doi.org/10.1038/s41596-025-01141-z
  28. Nat Commun. 2025 Mar 26. 16(1): 2972
    Cryo-EM structures of a protein pore reveal a cluster of cholesterol molecules and diverse roles of membrane lipids.
    Gašper Šolinc, Marija Srnko, Franci Merzel, Ana Crnković, Mirijam Kozorog, Marjetka Podobnik, Gregor Anderluh.
      The structure and function of membrane proteins depend on their interactions with lipids that constitute membranes. Actinoporins are α-pore-forming proteins that bind preferentially to sphingomyelin-containing membranes, where they oligomerize and form transmembrane pores. Through a comprehensive cryo-electron microscopic analysis of a pore formed by an actinoporin Fav from the coral Orbicella faveolata, we show that the octameric pore interacts with 112 lipids in the upper leaflet of the membrane, reveal the roles of lipids, and demonstrate that the actinoporin surface is suited for binding multiple receptor sphingomyelin molecules. When cholesterol is present in the membrane, it forms a cluster of four molecules associated with each protomer. Atomistic simulations support the structural data and reveal additional effects of the pore on the lipid membrane. These data reveal a complex network of protein-lipid and lipid-lipid interactions and an underrated role of lipids in the structure and function of transmembrane protein complexes.
    DOI:  https://doi.org/10.1038/s41467-025-58334-z
  29. Gut. 2025 Mar 23. pii: gutjnl-2024-333638. [Epub ahead of print]
    Endothelial-like cancer-associated fibroblasts facilitate pancreatic cancer metastasis via vasculogenic mimicry and paracrine signalling.
    Xugang Sun, Wenrun Cai, Haorui Li, Chuntao Gao, Xi Ma, Yu Guo, Danqi Fu, Di Xiao, Zhaoyu Zhang, Yifei Wang, Shengyu Yang, Yukuan Feng, Tiansuo Zhao, Jihui Hao.
       BACKGROUND: Cancer-associated fibroblasts (CAFs) are highly heterogeneous in the progression of pancreatic ductal adenocarcinoma (PDAC) and vasculogenic mimicry (VM) refers to a phenomenon in which cancer cells adopt endothelial-like characteristics.
    OBJECTIVE: To identify a novel protumoural CAF subtype undertaking VM.
    DESIGN: We used single-cell RNA sequencing and mIHC to identify FAPα+CD144+ endothelial-like CAFs (endoCAFs) and combined prospective and retrospective analyses to assess its clinical outcomes. Tube formation, proliferation and invasion assay were conducted on cell lines, organoids, the orthotopic tumour model and LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model. Mechanically, we performed cytokine array assays, RNA-sequencing, IP-mass spectrometry, ChIP and luciferase analyses. Importantly, an siRNA delivery nanosystem was developed to precisely target FAPα+CD144+endoCAFs in vivo.
    RESULTS: FAPα+CD144+endoCAFs were present in the tumour microenvironment of PDAC, and patients with a higher CD144+CAFs proportion displayed poor prognosis of PDAC. FAPα+CD144+endoCAFs not only acquired a VM phenotype to provide metastatic conduits but also promoted the proliferation and invasion of tumour cells in situ through paracrine signalling, thereby actively facilitating the metastasis of tumour cells. The CD144-β-catenin-STAT3 signalling axis was activated, and CD144 and downstream secreted cytokines were transcriptionally upregulated to maintain the dual roles of endoCAFs. A CAF-targeting siRNA delivery nanosystem, via loading FAPα and siCD144, was administered to precisely target FAPα+CD144+ endoCAFs, which substantially inhibited their protumoural roles in vivo.
    CONCLUSION: FAPα+CD144+endoCAFs can promote metastasis of PDAC via undertaking VM and paracrine through activation of the CD144-β-catenin-STAT3 signalling axis. CAF-targeting siRNA delivery nanosystem can inhibit tumour progression by precisely targeting FAPα+CD144+endoCAFs.
    Keywords:  LIVER METASTASES; MOLECULAR ONCOLOGY; PANCREATIC CANCER; PANCREATIC FIBROSIS
    DOI:  https://doi.org/10.1136/gutjnl-2024-333638
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