bims-cagime 2026-05-31 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–05–31
28 papers selected by
Kıvanç Görgülü, Technical University of Munich

Mammalian Lysophagy: mechanisms and pathophysiological implications.
A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.
Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence.
Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis.
Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.
Metabolic plasticity in the pancreatic cancer metastatic cascade.
Amoeboid cancer cells at a glance.
Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: a randomized, multiarm, run-in phase trial.
NF-κB inducing kinase (NIK) deletion accelerates KRAS-driven pancreatic cancer in association with tumor microenvironment remodeling.
Regulation of Ferroptosis Sensitivity in Hepatocellular Carcinoma Cells by Lysosomal Ion Channels TPC2 and TRPML1.
CLIC-dependent internalization of caveolin-1 to lysosomal vacuoles in response to osmotic regulation.
Pro-aging effects of chronic glucocorticoid signaling.
KMT2D depletion promotes KRAS-induced pancreatic carcinogenesis independent of TP53.
An appendiceal cancer organoid biobank identifies phenotypic evolution and druggable dependencies of peritoneal carcinomatosis.
Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.
Mesenchymal drift: A convergent framework for the hallmarks of aging.
Capillary bifurcations mechanically dissociate clusters of tumor cells.
Mitochondria-lysosome coupling contributes to lysosome acidification and aging.
Breaking the membrane heredity paradox through de novo protocell formation.
Formation of Liver Metastases Is Accompanied by Accelerated Musculoskeletal Deficits in LLC Tumor Hosts.
Dehydration promotes intracellular lipid synthesis and accumulation.
AI-discovered protein fragments as generalizable regulators of biomolecular condensates.
Farnesylation-driven KRAS phase separation promotes colon tumor growth.
Monitoring Cell Membrane Hydration Using a Fluorescent Probe Sensitive to Trace Water.
Do you want to live forever? Lessons learned from the biology of aging.
Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples.
Multicellular senescence impairs skeletal muscle recovery following disuse in aging.
Organelle scaling over a 100-fold cell size range.

Autophagy. 2026 May 25.

Mammalian Lysophagy: mechanisms and pathophysiological implications.

Fujian Ji, Mingran Dai, Zimu Wang, Enyong Dai, Rui Kang, Daniel J Klionsky, Daolin Tang, Yan Huang, Yu Sun, Liu Tong.

  Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.

Keywords:  Autophagy receptor; disease; lysophagy; lysosomes; repair

DOI:  https://doi.org/10.1080/15548627.2026.2679642
Mol Cell. 2026 May 29. pii: S1097-2765(26)00311-4. [Epub ahead of print]

A multi-subunit autophagic capture complex facilitates degradation of ER-stalled MHC class I in pancreatic cancer.

Marine Berquez, Alexander L Li, Matthew A Luy, Anthony C Venida, Simon McDowall, Thomas O'Loughlin, Gilles Rademaker, Abhilash Barpanda, Jingjie Hu, Julian Yano, Arun P Wiita, Luke A Gilbert, Peter M Bruno, Rushika M Perera.

  Pancreatic ductal adenocarcinoma (PDAC) evades immune surveillance in part through autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I), though the basis for this vulnerability is unclear. Using synchronized endoplasmic reticulum (ER) exit assays, we show that PDAC cells retain MHC-I in the ER and inefficiently traffic it to the plasma membrane. We identify an autophagic capture complex composed of the ER-phagy receptor TEX264 and the cargo receptor NBR1 that targets MHC-I for degradation. Suppression of either receptor restores total and surface MHC-I levels. Capture is linked to antigen loading, as impaired peptide loading increases MHC-I binding to the TEX264-NBR1 complex, while high-affinity peptides reduce binding and promote increased surface localization. A genome-wide CRISPRi screen identified the ER-localized E3 ligase NFXL1 as a mediator of MHC-I ubiquitylation and capture. Elevated NFXL1 correlates with reduced MHC-I expression and poor prognosis, highlighting a targetable pathway regulating PDAC immunogenicity.

Keywords:  ER-phagy; MHC-I; autophagy; lysosome; pancreatic cancer

DOI:  https://doi.org/10.1016/j.molcel.2026.05.005
Cell Death Differ. 2026 May 26.

Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence.

Markus S Hess, Kamal M Al-Shami, Carolina Dehesa Caballero, Julie Haenlin, Adriano B Chaves-Filho, Lisa Schlicker, Philipp Poeller, Felix C E Vogel, Ioanna Koltsaki, Deniz Gedik, Marta Campos Alonso, Susanne Walz, Carsten P Ade, Martin Eilers, Beate K Straub, Jochen S Utikal, Svenja Meierjohann, Mathias T Rosenfeldt, Marteinn T Snaebjornsson, Almut Schulze.

Oncogene-induced senescence (OIS), a cellular programme initiated by activation of oncogenic signalling, provides a barrier to transformation and is accompanied by major reprogramming of cellular metabolism. We show here that induction of OIS by BRAFV600E expression in human diploid fibroblasts led to global changes in the cellular lipidome, characterised by a strong increase in triglycerides (TG) and a marked reduction in membrane phosphoglycerides carrying polyunsaturated fatty acids (PUFA) in their acyl-chains. Induction of BRAFV600E OIS resulted in a marked resistance towards lipid peroxidation and ferroptosis. Inhibition of TG synthesis by blocking diacylglycerol O-acyltransferase 1 (DGAT1) resulted in PUFA re-distribution to membrane lipids and increased ferroptosis sensitivity of senescent cells. Inhibition of DGAT also altered the senescence-associated secretory phenotype (SASP) and enhanced the secretion of oxylipins by BRAFV600E OIS cells. Combined blockade of DGAT1-dependent TG and COX2-dependent oxylipin synthesis fully restored ferroptosis sensitivity in BRAFV600E OIS cells. Together, these findings indicate that channelling of PUFA towards TG synthesis confers protection from oxidative stress and ferroptosis during BRAFV600E OIS but also limits the production of pro-inflammatory lipid mediators, a key feature of the senescent phenotype.

DOI: https://doi.org/10.1038/s41418-026-01766-x
Sci Adv. 2026 May 29. 12(22): eaeb2368

Metabolic rewiring driven by phosphoglycolate phosphatase deletion inhibits ferroptosis.

Marian Brenner, Sina Höhlein, Paul Wirth, Leon Neidt, Melina Lappe, Elisa Hopke, Eirini Sfakianaki, Martina Fischer, Kerstin Hadamek, Angelika Keller, Sebastian Bothe, José Pedro Friedmann Angeli, Anna M Schmoker, Arminja N Kettenbach, Agnes Fekete, Werner Schmitz, Ingrid Tessmer, Elisabeth Jeanclos, Antje Gohla.

Modulating ferroptosis, a form of cell death driven by uncontrolled lipid peroxidation, is of interest in numerous diseases. Here, we found that the deletion of phosphoglycolate phosphatase (PGP), an essential enzyme that safeguards high glycolytic flux, suppresses ferroptosis. Using metabolomic and isotopic labeling experiments together with lipid and proteomic profiling, we find that PGP loss drives a rewiring of the pentose phosphate pathway and of cellular energy and lipid metabolism that triggers a multifactorial antioxidant response. Paradoxically, our attempts to block PGP pharmacologically led to the realization that the recently described PGP inhibitor compound 1 (CP1) exerts a strong ferroptosis-sensitizing effect. Using genetic, biochemical, and biophysical approaches, we characterize CP1 as a direct, species-independent, dual inhibitor of PGP and ferroptosis suppressor protein 1 (FSP1), and further find that CP1 triggers FSP1 self-assembly. In sum, we identify PGP as a target protein for ferroptosis control and introduce a small-molecule FSP1 inhibitor with unique features to the armamentarium of pharmacological ferroptosis modulators.

DOI: https://doi.org/10.1126/sciadv.aeb2368
Nat Cell Biol. 2026 May 26.

Membrane bridges and nanodomain partitioning govern membrane protein targeting to lipid droplets.

Arda Mizrak, Jacob Kæstel-Hansen, Jessica Matthias, J Wade Harper, Nikos S Hatzakis, Robert V Farese, Tobias C Walther.

Numerous metabolic enzymes translocate from the endoplasmic reticulum (ER) membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease. However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood. Here using minimal fluorescence photon fluxes nanoscopy and highly inclined and laminated optical single-molecule tracking combined with machine learning, we show that HSD17B13, GPAT4 and the model cargo 'LiveDrop' diffuse at comparable speeds in the ER and on LDs, but become nano-confined upon reaching the LD surface. Mechanistic dissection of LiveDrop targeting revealed that this confinement, along with protein accumulation on LDs, depends on specific residues within its targeting motif. These residues mediate preferential interactions with nanoscale membrane domains, suggesting that LD-targeted proteins selectively partition into distinct lipid-protein environments that transiently alter local motion and concentrate them at the LD surface. Single-molecule trajectories further revealed bidirectional trafficking of LiveDrop across seipin-containing ER-LD bridges, providing direct evidence for lateral protein transfer across membrane contact sites. These findings establish nanodomain-based confinement as a key mechanism driving selective protein accumulation on LDs and reveal how membrane bridges between organelles facilitate protein sorting.

DOI: https://doi.org/10.1038/s41556-026-01963-3
Biochim Biophys Acta Rev Cancer. 2026 May 27. pii: S0304-419X(26)00094-6. [Epub ahead of print] 189622

Metabolic plasticity in the pancreatic cancer metastatic cascade.

Biwen Zhu, Yibing Guo, Yuhua Lu.

  Most deaths from pancreatic ductal adenocarcinoma (PDAC) result from metastatic organ failure rather than primary tumor burden. Across the metastatic cascade, tumor cells encounter hypoxia, nutrient limitation, oxidative stress, immune pressure, and changing stromal conditions, and only those capable of dynamic metabolic adaptation successfully disseminate and colonize distant sites. In this review, we summarize how metabolic plasticity shapes PDAC dissemination, organ-specific colonization, and metastatic outgrowth. We further discuss how this framework may shift therapeutic strategy from broad metabolic blockade toward precision interventions that target metastatic fitness.

Keywords:  Metastatic plasticity; Pancreatic ductal adenocarcinoma (PDAC); Therapeutic targets; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189622
J Cell Sci. 2026 May 15. pii: jcs264674. [Epub ahead of print]139(10):

Amoeboid cancer cells at a glance.

Ritobrata Ghose, Victoria Sanz-Moreno.

  Amoeboid behaviour represents a distinct and clinically significant cancer cell state within the epithelial-to-mesenchymal transition (EMT) spectrum. Defined by the loss of cell-cell junctions and adoption of a rounded morphology, amoeboid cancer cells exhibit low adhesion and rely heavily on Rho-ROCK-myosin II-mediated cortical contractility. This combination of high contractility and reduced adhesion enables rapid migration through dense, confining environments, using blebs as functional protrusions. This behaviour is commonly observed at tumour invasive fronts, within metastatic deposits and among therapy-resistant cell populations. Amoeboid identity integrates multiple biochemical signalling programmes alongside mechanical cues such as confinement, matrix topography and shear stress. Collectively, these factors drive a highly plastic state characterised by stem-cell-like traits, metabolic adaptability, low oxidative stress and an immunosuppressive secretome. Such features confer strong metastatic potential and broad resistance to therapy, underpinned by core physicochemical dependencies on cortical tension, membrane mechanics and redox balance. This Cell Science at a Glance article and the accompanying poster highlight these defining characteristics, establishing amoeboid behaviour as a crucial driver of cancer progression and an increasingly promising therapeutic target.

Keywords:  Amoeboid cancer cells; Cytoskeleton; Immunomodulation; Mechanobiology; Metastasis

DOI:  https://doi.org/10.1242/jcs.264674
Nat Cancer. 2026 May 25.

Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: a randomized, multiarm, run-in phase trial.

Kimberly J Perez, Andressa Dias Costa, Alexander Jordan, Thomas B Karasic, Dalia Elganainy, Suryun Kim, Chen Yuan, Dan Y Gui, Runzi Tan, Sung Chul Hong, Xi Wang, Simona Cristea, Emma Coleman, Morgan Truitt, Tae Gyu Oh, Hui Zheng, C Sloane Furniss, Lauren Brais, Alexandra Bird, Josh Remland, Vasilena Gocheva, Jennifer S Thalappillil, Mark Anderson, James M Cleary, Andrea Enzinger, Marios Giannakis, Kimmie Ng, Douglas A Rubinson, Benjamin Schlechter, Rishi Surana, Harshabad Singh, Thomas Abrams, Ursina Teitelbaum, Natallia Izgur, Eliezer Allen, Peter S Winter, Srivatsan Raghavan, Jen Jen Yeh, Daniel Von Hoff, Christopher Liddle, Michael Downes, Ronald M Evans, Peter O'Dwyer, Andrew Aguirre, Jonathan A Nowak, Brian M Wolpin.

Vitamin D receptor (VDR) agonists promote quiescence of cancer-associated fibroblasts and improve efficacy of chemotherapy in preclinical models of pancreatic cancer. We conducted a run-in phase trial with primary endpoint of safety when the VDR agonist paricalcitol is given with first-line gemcitabine and albumin-bound paclitaxel (GA) in patients with metastatic pancreatic cancer. Secondary endpoints included pharmacodynamic analyses. Thirty-six patients were randomized to GA plus placebo, GA plus intravenous paricalcitol or GA plus oral paricalcitol with pretreatment and on-treatment tumor biopsies. Paricalcitol was safely administered with GA, although five patients (42%) receiving oral paricalcitol had grade 2-4 hypercalcemia and required dose reduction. Nuclear VDR protein expression was heterogeneous across patients, and VDR was expressed in tumor, immune and stromal cells. Compared to pretreatment specimens, on-treatment biopsies had decreased proportion of αSMA+ fibroblasts, altered fibroblast VDR activation signature and greater density and spatial colocalization of CD8+ T cells with tumor cells in the GA-plus-paricalcitol arms. VDR expression was predictive of tumor response in the GA-plus-paricalcitol arms. Paricalcitol can be safely administered with chemotherapy to patients with metastatic pancreatic cancer, and on-treatment biopsies indicated favorable modulation of the tumor microenvironment by paricalcitol as predicted by preclinical models. ClinicalTrials.gov identifier: NCT03520790 .

DOI: https://doi.org/10.1038/s43018-026-01165-8
Cell Death Dis. 2026 May 27. pii: 513. [Epub ahead of print]17(1):

NF-κB inducing kinase (NIK) deletion accelerates KRAS-driven pancreatic cancer in association with tumor microenvironment remodeling.

Ziwei Du, Ulrike F G Büttner, Hannah Lea Wirth, Melanie Gerstenlauer, Uta Manfras, Rikarda Loidl, Doğa Bahçeci, Katja Steiger, Thomas Metzler, Lap Kwan Chan, Miltiadis Tsesmelis, Thomas Wirth.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by dense stroma, immune suppression, and therapy resistance. While canonical NF-κB signaling has been extensively studied in PDAC, the non-canonical pathway and its key kinase, NF-κB-inducing kinase (NIK), remain less characterized. Here, we employed genetically engineered mouse models, including Pdx1-Cre; KRASG12D (KC), Pdx1-Cre; KRASG12D; p53fl/fl (KPC), and their NIK-deficient counterparts (KNiC and KPNiC). To mimic inflammation-driven tumorigenesis observed in human PDAC, we administered cerulein in the KC and KNiC mice to induce pancreatitis and promote lesion progression. We found that NIK deletion accelerated lesion formation, progression to high-grade PanINs and invasive carcinoma in both KC and KPC backgrounds. Despite similar tumor grade and burden at endpoint, KPNiC mice exhibited shortened survival compared to controls, indicating that NIK acts as a tumor-suppressor and limits early-stage tumor progression. Mechanistically, NIK loss was associated with elevated ERK signaling that increased lesion cell proliferation, and also reduced acinar cell death following pancreatitis. In the tumor microenvironment, NIK deletion promoted myofibroblast activation and enrichment of myCAF-associated gene expression, likely through secondary activation of canonical NF-κB and pro-fibrotic signaling pathways such as TGF-β, Wnt, and FGF. Finally, increased IL6-STAT3 signaling and neutrophil infiltration were observed, suggesting broader immunostromal remodeling in the absence of NIK. Consistent with these findings, analysis of TCGA-PAAD data showed that low NIK expression correlates with poor overall survival in human PDAC. These findings reveal a tumor-suppressive role of NIK in pancreatic cancer and underscore the need for caution in targeting NF-κB signaling, as balanced pathway activity appears critical for regulating early tumor progression and microenvironmental interactions in PDAC.

DOI: https://doi.org/10.1038/s41419-026-08877-w
Antioxidants (Basel). 2026 May 13. pii: 618. [Epub ahead of print]15(5):

Regulation of Ferroptosis Sensitivity in Hepatocellular Carcinoma Cells by Lysosomal Ion Channels TPC2 and TRPML1.

Franz Geisslinger, Victoria Gell, Finja Witt, Dawid Jaślan, Christian Grimm, Andreas Koeberle, Karin Bartel.

  Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a therapeutic vulnerability in hepatocellular carcinoma (HCC), yet the contribution of lysosomes to this process remains incompletely understood. In this study, we investigated whether lysosomal ion channels regulate ferroptosis sensitivity in HCC cells, focusing on the two-pore channel 2 (TPC2) and the transient receptor potential mucolipin 1 (TRPML1). Using pharmacological modulation, genetic knockout models, flow cytometry-based cell death and lipid peroxidation assays, lipidomics, calcium measurements, and molecular analyses across multiple HCC cell lines, we examined how these channels influence ferroptotic signaling. We show that NAADP-dependent TPC2 activity is required for efficient ferroptosis induction, whereas TPC2 loss renders HCC cells resistant to ferroptosis triggered by system Xc- inhibition or glutathione peroxidase 4 (GPX4)blockade. This resistance is associated with reduced lipid peroxidation, altered calcium signaling, and selective depletion of polyunsaturated phosphatidylethanolamine species linked to decreased Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) expression. In contrast, TRPML1 deficiency sensitizes cells to ferroptosis and correlates with enhanced endoplasmic reticulum stress and oxidative imbalance rather than major lipid remodeling. Collectively, these findings identify lysosomal ion channels as key modulators of ferroptosis in HCC and highlight distinct mechanisms by which TPC2 and TRPML1 regulate cellular redox balance and death susceptibility.

Keywords:  ACSL4; TPC2; TRPML1; calcium signaling; ferroptosis; hepatocellular carcinoma; lipid peroxidation; lysosomes; oxidative stress; redox biology

DOI:  https://doi.org/10.3390/antiox15050618
Cell Rep. 2026 May 23. pii: S2211-1247(26)00451-1. [Epub ahead of print]45(6): 117373

CLIC-dependent internalization of caveolin-1 to lysosomal vacuoles in response to osmotic regulation.

Timothy H Wong, Matheus F Lima, Aditya Nagrath, Y Lydia Li, Bharat Joshi, FuiBoon Kai, Ivan Robert Nabi.

  Originally thought to be a major endocytic portal, caveolae function as a membrane buffer, whereby caveolae flattening protects the plasma membrane from rupture under mechanical stress, such as hypotonic shock. However, the fate of the caveolae coat protein caveolin-1 upon caveolae flattening is not known. Here, extended hypotonic shock induces ubiquitin-independent, CLIC-dependent endocytosis of caveolin-1 to large, intracellular, CD44-positive, pH-neutral lysosomal vacuoles negative for multivesicular body markers. Caveolin-1 recycles from these vacuoles to the plasma membrane upon return to isotonic conditions. Caveolin-1 internalization occurs upon reduced cell volume due to extended hypotonic shock as well as in low-tension cells grown on reduced-stiffness hydrogels. Upon hypertonic shock, caveolin-1 internalization occurs in PC3 cells, lacking cavin-1 and caveolae, and is inhibited upon cavin-1 reintroduction. CLIC endocytosis of non-caveolar caveolin-1 to neutral pH lysosomal vacuoles identifies a non-caveolar endocytic and recycling pathway for caveolin-1 in response to reduced membrane tension.

Keywords:  CD44; CLIC endocytosis; CP: cell biology; caveolae; caveolin-1; lysosomal vacuole; lysosome; mechanical stress; osmotic shock; super resolution microscopy

DOI:  https://doi.org/10.1016/j.celrep.2026.117373
Cell Metab. 2026 May 28. pii: S1550-4131(26)00187-7. [Epub ahead of print]

Pro-aging effects of chronic glucocorticoid signaling.

Flavia Lambertucci, Frederic Castinetti, Isabelle Martins, Carlos López-Otín, Guido Kroemer.

  Glucocorticoids (GCs) are essential endocrine regulators coordinating stress responsiveness, metabolic flexibility, inflammatory resolution, and circadian physiology. While acute GC fluctuations are adaptive, sustained exposure (arising from psychosocial stress, circadian disruption, obesity, chronic inflammation, neoplasms, or steroid therapy) elicits pleiotropic effects that overlap with biological aging. Prolonged GC signaling intersects with multiple hallmarks of aging by altering nutrient sensing, suppressing autophagy, impairing mitochondrial quality control, and promoting cellular senescence. In this context, the GC-responsive polypeptide ACBP/DBI (acyl-coenzyme A [CoA]-binding protein/diazepam-binding inhibitor) has emerged as a stress-induced inhibitor of macroautophagy that amplifies several metabolic and immune consequences of GC excess linked to aging phenotypes. Clinically, chronic GC elevation is associated with earlier and more severe manifestations of age-related diseases, including metabolic syndrome, osteoporosis, sarcopenia, neurodegeneration, cardiovascular disease, immunosenescence, and cancer. Here, we review mechanistic links between GC signaling and systemic aging and discuss strategies to mitigate the age-accelerating consequences of persistent GC exposure.

Keywords:  Cushing syndrome; corticosteroid; hallmarks of aging; hypercortisolism; multimorbidity; neuroendocrine system

DOI:  https://doi.org/10.1016/j.cmet.2026.05.002
J Biol Chem. 2026 May 27. pii: S0021-9258(26)02075-2. [Epub ahead of print] 113203

KMT2D depletion promotes KRAS-induced pancreatic carcinogenesis independent of TP53.

Ezequiel J Tolosa, Glancis L Raja Arul, Ashley N Sigafoos, Victoria Ferrero, David R Pease, Luciana L Almada, Renzo E Vera, Nicole M Pena Ruiz, Tara L Hogenson, Kayla C LaRue-Nolan, Brooke R Tader, Rondell P Graham, Mathew Brown, Catherine E Hagen, Aleksey V Matveyenko, Ryan M Carr, Kai Ge, Martin E Fernandez-Zapico.

  Despite extensive efforts identifying disease drivers, therapeutics developed against them have so far failed to improve patient outcomes in pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. Thus, focus has turned to the characterization of molecules contributing to the drivers' ability to promote the development of this disease. Here, we demonstrate a novel role for KMT2D, a histone methyltransferase, in PDAC biology. Analysis of exome-seq and RNA-Seq data shows that KMT2D is highly mutated and significantly downregulated in human PDAC. Further, low KMT2D expression associates with lower survival in human PDAC. Next, we examined the role Kmt2d in PDAC development using two independent genetically engineered mouse models driven by mutant Kras in the presence and absence of the tumor suppressor Tp53. Loss Kmt2d increase tumor incidence mostly with a poorly differentiated phenotype and reduces survival in both models even in absence of Tp53. Similarly, in human PDAC, the loss of TP53 does not affect the survival of KMT2D low cases. Of note, the sole Kmt2d depletion did not affect normal pancreas development or mice survival. RNA-Seq analysis demonstrates the enrichment of pathways controlling cell growth in Kmt2df/+ PDAC cells. Interestingly, inactivation of Kmt2d resulted in increased levels of Ki67 positive cells in vivo. Together, these findings define the role of this methyltransferase in Kras-driven PDAC biology as tumor suppressor candidate for this dismal condition.

Keywords:  KMT2D; KRAS; gene expression; pancreatic cancer; tumor suppression

DOI:  https://doi.org/10.1016/j.jbc.2026.113203
Dev Cell. 2026 May 26. pii: S1534-5807(26)00161-9. [Epub ahead of print]

An appendiceal cancer organoid biobank identifies phenotypic evolution and druggable dependencies of peritoneal carcinomatosis.

Ahmed Mahmoud, Christine Sukhwa, Michael Giarrizzo, Philip H Choi, Jura Pintar, Henry Walch, Nan Zhao, Jonathan Bermeo, Sebastian Chung, Manisha Raghavan, Samhita Bapat, Qingwen Jiang, Julia Meredith, Canan Firat, Andrea Cercek, Michael B Foote, Nikolaus Schultz, Walid K Chatila, Garrett M Nash, Jinru Shia, Francisco Sanchez-Vega, Steven Larson, Arvin C Dar, Neal Rosen, Georgios Karagkounis, Karuna Ganesh.

  Peritoneal carcinomatosis (PC) is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), which metastasizes almost exclusively to the peritoneum. No stable preclinical models of AC exist, limiting drug discovery and representing an unmet clinical need. We establish a stable biobank of 16 long-term cultured AC patient-derived tumor organoids (PDTOs). We establish an organoid orthotopic intraperitoneal xenograft model that recapitulates diffuse PC and show that PC organoids retain increased metastatic capacity, decreased growth-factor dependency, and decreased sensitivity to standard-of-care chemotherapy relative to matched primary AC organoids. Single-cell profiling reveals dedifferentiation from differentiated states in primary AC into intestinal stem cell and fetal progenitor states in AC-PC, with upregulation of oncogenic signaling pathways. We identify KRASMULTI-ON inhibitor RMC-7977 and the Wnt-targeting tyrosine kinase inhibitor WNTinib as clinically actionable strategies to target AC-PC more effectively.

Keywords:  KRAS inhibitor; appendiceal cancer; genomics; growth factor dependencies; intratumor heterogeneity; mouse model; organoids; peritoneal carcinomatosis; targeted therapies

DOI:  https://doi.org/10.1016/j.devcel.2026.04.014
Cell Metab. 2026 May 27. pii: S1550-4131(26)00185-3. [Epub ahead of print]

Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.

Chesta Jain, Muqit Essani, Roshan Kumar, Nupur K Das, Rashi Singhal, Nicholas J Rossiter, Brandon Chen, Wesley Huang, Zheng Hong Lee, Sumeet Solanki, Yuezhong Zhang, Peter Sajjakulnukit, Li Zhang, Prarthana J Dalal, David A Hanna, Cristina Castillo, Harrison S Greenbaum, Shannon E McCollum, Elena M Stoffel, Joel K Greenson, L James Maher, Costas A Lyssiotis, Ruma Banerjee, Yatrik M Shah.

  Colorectal cancer (CRC) cells are addicted to iron, which fuels nucleotide synthesis, mitochondrial respiration, and proliferation. Yet paradoxically, high intracellular iron is cytotoxic to most cells, raising the question of how CRC cells tolerate and exploit iron-rich environments. Ferroptosis, an iron-dependent form of cell death, is thought to mediate iron toxicity. However, whether most ferroptosis regulators, identified through synthetic chemical screens or small molecule activators, play a role in modulating iron toxicity, particularly in vivo, remains unclear. Here, using multi-omics profiling, CRISPR screening, and in vivo models, we uncover a heme-succinate dehydrogenase (SDH)-coenzyme Q (CoQ) axis that enables CRC cells to buffer iron-induced oxidative stress. Heme-dependent SDH reduces CoQ, which redistributes to mitochondrial and plasma membranes to detoxify lipid reactive oxygen species (ROS) as a radical-trapping antioxidant. These findings reveal that CRCs co-opt metabolic cofactors both for growth and for survival under physiologically toxic iron levels, uncovering new vulnerabilities for therapy.

Keywords:  colorectal cancer; iron toxicity; mitochondrial antioxidant; oxidative stress

DOI:  https://doi.org/10.1016/j.cmet.2026.04.020
Cell. 2026 May 28. pii: S0092-8674(26)00455-1. [Epub ahead of print]189(11): 3184-3213

Mesenchymal drift: A convergent framework for the hallmarks of aging.

Jinlong Y Lu, William B Tu, Shuai Ma, Zaijun Ma, Ivan Imaz-Rosshandler, Mingxi Weng, Jing Qu, Concepcion Rodriguez Esteban, Pradeep Reddy, Guang-Hui Liu, Juan Carlos Izpisua Belmonte.

  Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift, a process in which cells progressively lose lineage identity and adopt mesenchymal features, as a convergent framework that integrates the hallmarks of aging. Accumulating evidence suggests that mesenchymal drift can both arise from and reinforce these hallmarks, forming a feedback network that drives systemic decline. Framing aging through mesenchymal drift shifts the focus from discrete molecular defects to interconnected disruptions in cellular identity and cell state regulation, providing a more cohesive view of aging biology. Mesenchymal drift may therefore represent a measurable and targetable mechanism underlying diverse age-related pathologies. Interventions such as partial reprogramming may restrain mesenchymal drift, restore cellular identity, and simultaneously counteract multiple hallmarks, positioning it as both a convergent nexus and a tractable therapeutic axis in aging biology.

Keywords:  Yamanaka factors; aging; biomarkers; cellular identity and plasticity; endothelial-to-mesenchymal transition; epithelial-to-mesenchymal transition; fibrosis; geroscience; partial reprogramming; rejuvenation

DOI:  https://doi.org/10.1016/j.cell.2026.04.020
PNAS Nexus. 2026 May;5(5): pgag166

Capillary bifurcations mechanically dissociate clusters of tumor cells.

Angelos Vrynas, Aisher Chen, Georgia Kontaxi, Sam H Au.

  Circulating tumor cell (CTC) clusters are major drivers of cancer metastasis, possessing higher metastatic potential than equal numbers of single CTCs. While their ability to traverse linear capillary segments has been studied, their transit behaviors in capillary bifurcations remain poorly understood. We utilized live-cell imaging and microfluidic devices that replicate the diverse geometries of human capillary bifurcations to investigate the transit dynamics of breast cancer clusters. We demonstrate that clusters dissociate into smaller clusters and single cells and that this phenomenon is strongly influenced by geometric features of equal and small-sized daughter channels in capillary bifurcations. Moreover, inhibition of actin polymerization increases both the frequencies of cluster dissociation and cell lysis during cluster transit in capillary bifurcations. Overall, our findings suggest that capillary biomechanics and actin filament polymerization affect the integrity of CTC clusters.

Keywords:  actin cytoskeleton; cancer metastasis; capillary bifurcations; circulating tumor cell clusters; microfluidics

DOI:  https://doi.org/10.1093/pnasnexus/pgag166
Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]

Mitochondria-lysosome coupling contributes to lysosome acidification and aging.

Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.

  Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.

Keywords:  Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification

DOI:  https://doi.org/10.1016/j.molcel.2026.05.004
Nat Commun. 2026 May 28.

Breaking the membrane heredity paradox through de novo protocell formation.

Satyam Khanal, Alessandro Fracassi, Alexander Harjung, Michael D Burkart, Neal K Devaraj.

Lipid membranes define cell boundaries, acting as gatekeepers for transport and signaling. A central paradigm in biology is that all cellular membranes descend from a common ancestral membrane, as they cannot be generated in the absence of pre-existing lipid structures. It is thus unclear whether lipid membranes can arise from membrane-less precursors. Here we demonstrate the de novo generation of lipid bilayers in the absence of any pre-existing membranes, membrane-bound proteins, or lipid nanostructure templates. Using acetate and cysteine as simple metabolites, lipid tails are constructed by soluble enzymes and spontaneously form diacyl lipids that assemble into vesicles. Pore-forming peptides facilitate precursor transport into vesicles, allowing the continuous generation of new lipids. Formation of glycolipid membranes creates compartments that can maintain proton gradients. Our findings demonstrate that lipid compartments can form without pre-existing membranes, establishing a unique route linking lipid synthesis to compartment formation and function.

DOI: https://doi.org/10.1038/s41467-026-73667-z
Int J Mol Sci. 2026 May 15. pii: 4426. [Epub ahead of print]27(10):

Formation of Liver Metastases Is Accompanied by Accelerated Musculoskeletal Deficits in LLC Tumor Hosts.

Paola Ortiz Gonzalez, Anna M Miller, Luis F Cardona Polo, Lilian I Plotkin, Fabrizio Pin, Joshua R Huot.

  Lung cancer is a leading cause of death worldwide and is often accompanied by declines in musculoskeletal health (i.e., cachexia). Despite affecting a majority of lung cancer patients, cachexia remains understudied and currently has no cure. We have previously demonstrated that liver metastases (LMs) exacerbate cachexia in murine models of colorectal cancer, and, while the liver represents a common site of metastases and is associated with poor prognosis in patients with lung cancer, whether LMs heighten musculoskeletal wasting in mice bearing lung cancer is unknown. Here, we aimed to characterize the impact of LMs on musculoskeletal health in a mouse model of lung cancer cachexia. C57BL/6J male mice were injected with LLC tumor cells either subcutaneously or intrasplenically (LMs) to mimic hepatic metastases (n = 6-9/group). Upon sacrifice, skeletal muscle, bone, and plasma were collected for morphological and molecular analyses. Consistently, compared to healthy controls, metastatic tumor hosts displayed greater reductions in muscle weights (~17%), in line with decreased muscle torque (~23%) and reduced muscle cross-sectional area (~10%). On a molecular level, skeletal muscle from mice bearing LMs had elevated levels of pStat3, Murf1, and Atrogin-1, suggesting enhanced protein catabolism. Similar to skeletal muscle, metastatic tumor hosts displayed greater losses in trabecular bone and increased skeletal fragility. Plasma proteomics identified 211 and 131 differentially expressed proteins in metastatic hosts compared to control animals and subcutaneous LLC hosts, respectively. Top regulated pathways in mice bearing LMs included neutrophil degranulation, BAG2 signaling, and cachexia signaling. Overall, our findings demonstrate that LMs are accompanied by accelerated musculoskeletal wasting and weakness in a mouse model of lung cancer cachexia. This work highlights the need for animal models that mimic advanced cancer, thus providing a better understanding of the mechanisms that mediate cachexia.

Keywords:  bone; cachexia; lung cancer; muscle; musculoskeletal health

DOI:  https://doi.org/10.3390/ijms27104426
Nat Commun. 2026 May 25.

Dehydration promotes intracellular lipid synthesis and accumulation.

Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don A Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter K Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.

Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration and the ensuing hypertonic stress directly regulate lipid synthesis is unknown. We show that hypertonic stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.

DOI: https://doi.org/10.1038/s41467-026-73534-x
bioRxiv. 2026 May 12. pii: 2026.05.08.723928. [Epub ahead of print]

AI-discovered protein fragments as generalizable regulators of biomolecular condensates.

Andrew Savinov, Jibin Sadasivan, Kyle J White, Jack D Rubien, Gene-Wei Li, Lindsay B Case.

Biomolecular condensates are a major driver of cellular organization; however, we lack a predictable and systematic approach to modulate the multivalent interactions underlying their formation. Here, we demonstrate that the AI-driven FragFold method enables robust and generalizable design of protein fragments to control biomolecular condensate formation. We apply this approach across diverse proteins: G3BP1, SARS-CoV-2 nucleocapsid, TDP-43, and focal adhesion kinase (FAK). Computationally screening 2,235 fragments, we selected 18 candidates for further investigation. Overall, we attain a 50% success rate (9/18 designs) in discovering condensate-controlling protein fragments, experimentally testing just 3-5 candidates per protein. For each condensate-forming protein, the success rate is at least 40%. Furthermore, FragFold-predicted fragment binding modes align with their condensate-inhibitory or -enhancing activities, revealing both known and newly identified interactions underlying condensate formation. In FAK, a condensate-inhibitory fragment uncovered a domain interaction required for phase separation, and mutational analysis validated its importance. Notably, this inhibitory fragment also suppresses FAK condensate formation in living mammalian cells. Together, these results establish AI-guided protein fragment discovery as a generalizable strategy to dissect and control the molecular interactions that govern biomolecular condensates.

DOI: https://doi.org/10.64898/2026.05.08.723928
Cell. 2026 May 27. pii: S0092-8674(26)00519-2. [Epub ahead of print]

Farnesylation-driven KRAS phase separation promotes colon tumor growth.

Xingwen Wang, Yi Zhang, Minqiao Lu, Yafan Gong, Tianqi Guan, Guixue Hou, Yutong Wei, Meiqi Wang, Hao Liu, Lisha Huang, Shanliang Zheng, Qingyu Lin, Wenxin Zhang, Zhiyuan Xiang, Jiangwen Ma, Li Li, Hongxue Meng, Xinyuan Tong, Hongbin Ji, Jian Huang, Ying Hu.

  Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is one of the most frequently activated driver genes across human cancers. We identified a regulatory mechanism where KRAS forms condensates in the cytoplasm through liquid-liquid phase separation (LLPS), driven by farnesylation at the C185 residue within its hypervariable region (HVR). These condensates are associated with advanced stages and poor outcomes in colon cancer. Functionally, KRAS condensates efficiently interact with Ras-converting enzyme 1 (RCE1), promoting RCE1 clustering, enhancing KRAS processing, and facilitating its translocation to the plasma membrane, which amplifies KRAS signaling and promotes tumor growth. Growth factor stimulation further elevates KRAS condensate formation, emphasizing its role in tumor biology. Therapeutically, screening US Food and Drug Administration (FDA)-approved drugs revealed that statins, particularly pitavastatin, disrupt KRAS LLPS by inhibiting farnesylation, effectively suppressing colon cancer growth and enhancing the efficacy of G12Ci treatment. These findings uncover LLPS as a mechanism regulating KRAS activity and provide a promising target for therapeutic intervention.

Keywords:  KRAS; RCE1; colon cancer; farnesylation; phase separation

DOI:  https://doi.org/10.1016/j.cell.2026.05.002
Adv Mater. 2026 May 28. e73546

Monitoring Cell Membrane Hydration Using a Fluorescent Probe Sensitive to Trace Water.

Zixu He, Diankai Liu, He Li, Wenjie Gao, Sijia Lu, Quan Tang, Jiawen Li, Xiaohua Li, Huimin Ma, Wen Shi.

  The interaction between the cell membrane and water plays an important role in maintaining membrane structure and function. However, direct observation of cell membrane hydration has remained challenging due to the lack of specific and sensitive fluorescent probes for trace water in the cell membrane. Here, we present RMDR (rhodamine-derivatized membrane deep red), a membrane-localized fluorescent probe that reports the membrane hydration through polarity-dependent changes in fluorescence lifetime. RMDR displays clear lifetime decreases with increasing local water content in the range of 0%-1%. Using RMDR, we visualized the increase of cell membrane hydration upon hypotonic stimulation and identified a spatial-temporal gradient change from the periphery to the center in cell clusters. In addition, the increased membrane hydration was also observed during cuproptosis and other lipid peroxidation processes. These findings demonstrate that RMDR enables the examination of membrane hydration dynamics in living cells and may facilitate investigations of water-associated processes in physiological and stress-related contexts.

Keywords:  cell membrane; cuproptosis; fluorescence lifetime microscopy; fluorescent probe; membrane hydration

DOI:  https://doi.org/10.1002/adma.73546
PLoS Biol. 2026 May;24(5): e3003835

Do you want to live forever? Lessons learned from the biology of aging.

William B Mair, Ines Alvarez-Garcia.

Aging affects us all, but we still do not know how the process evolves or if we can modulate its pace. This issue of PLOS Biology presents a Collection of articles that explores different aspects of aging, discussing what challenges still need to be overcome.

DOI: https://doi.org/10.1371/journal.pbio.3003835
medRxiv. 2026 May 11. pii: 2024.05.13.24307238. [Epub ahead of print]

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

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

The intricate interplay between somatic mutations and copy number alterations critically influences tumour evolution and patient prognosis. However, traditional genomic analyses often treat these alterations independently, overlooking gene mutant dosage - a key emergent property of their interaction. Here, we develop an innovative computational framework that infers mutation copy number and multiplicity directly from clinical targeted sequencing panels without requiring matched normal samples. Using this approach, we derived gene mutant dosage statistics for over 500,000 mutations across 60,000 clinical samples spanning 39 cancer types. By stratifying more than 20,000 patients according to mutant dosage across multiple oncogenes and tumour suppressor genes, we identified 46 tumour type-specific biomarkers predictive of overall survival. Notably, 13 of these biomarkers across 12 tumour types were undetectable using standard binary mutant/wild-type models. Additionally, 26 biomarkers were recurrently associated with metastatic spread in 10 tumour types, and 20 predicted organ-specific metastatic tropism in 5 tumour types. Alongside confirming known roles for established oncogenes and tumour suppressors, our method reveals, for the first time, gene mutant dosage patterns as independent predictors of prognosis, metastatic potential, and site-specific dissemination across diverse solid tumours. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis, holding the potential to foster biomarker discovery significantly.

DOI: https://doi.org/10.1101/2024.05.13.24307238
Sci Adv. 2026 May 29. 12(22): eaed5255

Multicellular senescence impairs skeletal muscle recovery following disuse in aging.

Paul-Emile Bourrant, Elena M Yee, Zachary J Fennel, Robert J Castro, Chad M Skiles, Jonathan J Petrocelli, Naomi M M P de Hart, Lisa A Lesniewski, Anna E Beaudin, Katsuhiko Funai, Christopher S Fry, Micah J Drummond.

Aged skeletal muscle has a diminished capacity to recover after disuse. Although muscle regrowth requires coordinated interactions between immune and progenitor cells, the mechanisms of impaired remodeling in aged skeletal muscle remain poorly understood yet possibly involve the accumulation of senescent cells. We used a flow cytometry approach coupled with scRNAseq to determine the muscle senescent cell identity and transcriptional landscape during skeletal muscle recovery following disuse atrophy. Young and aged mice underwent 14 days of hindlimb unloading followed by reloading (7 or 14 days). At recovery, old mice showed smaller myofibers and abnormal muscle macrophage dynamics corresponding to greater collagen content. These outcomes coincided with elevated markers of muscle senescence (p21 and γH2AX) and increased SPiDER-β-Gal+ cells, which inversely correlated with muscle mass. Single-cell resolution of SPiDER+ cells unmasked several senescent interstitial muscle vascular and stromal populations. Senescent interstitial cell populations were enriched in aged muscle and displayed a senescence-associated secretory phenotype (SASP) across multiple stromal, vascular, and immune cell types. Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse. These findings identify a multicellular senescence environment within the muscle interstitial niche as a hallmark of impaired muscle recovery following disuse.

DOI: https://doi.org/10.1126/sciadv.aed5255
bioRxiv. 2026 May 13. pii: 2026.05.13.724986. [Epub ahead of print]

Organelle scaling over a 100-fold cell size range.

Alison C E Wirshing, Daniel J Lew.

Cell size in a proliferating cell population generally varies over a limited range (∼2-4-fold). Within such populations, organelle content increases with cell size maintaining a relatively constant organelle density (amount per cell volume). However, cells of different types can differ greatly in cell size as well as in organelle composition. In such cases, it is often unclear to what degree, if any, the differences in organelle composition are due to the difference in cell size. In principle, this issue could be resolved by examining situations where a proliferating population of cells of the same cell type exhibit much greater size variation. Here we characterize how organelle content scales with cell volume in the polymorphic fungus, A. pullulans , whose proliferating cells span a ∼100-fold size range. We find that mitochondria and ER content increases in proportion to cell volume, while this is not the case for vacuoles and peroxisomes. Thus, organelle composition is affected by cell size in this system.

DOI: https://doi.org/10.64898/2026.05.13.724986