Biology subjects

Evert, M.

Publications and source records attributed to Evert, M..

4 recordsLinked to original sources

bioRxiv2026

Endogenous PROM1 activation redistributes liver cancer cells along a preexisting differentiation axis

CD133 is widely used as a marker of stem-like cells in hepatocellular carcinoma, yet its functional contribution remains incompletely defined. In PLC/PRF/5 cells, acute CRISPR activation of endogenous PROM1 suppresses hepatic programs, whereas PROM1 knockdown elicits an opposing hepatocyte-identity response, together defining a PROM1-responsive transcriptional axis. Single-cell profiling shows that this axis is preexisting and tracks endogenous PROM1 heterogeneity, separating a hepatocyte-like, PROM1-low compartment from a PROM1-enriched, less hepatocyte-like compartment. Sustained PROM1 activation reduces the hepatocyte-like compartment and shifts the population toward intermediate positions along this axis. Related transcriptional patterns are detectable in an independent HuH-7 dataset and a human HCC case. Endogenous ALFA tagging identifies candidate CD133-associated proteins. Together, these findings support CD133 as an active contributor to tumor-cell state redistribution, extending its role beyond a mere marker of stem-like populations.

cancer biology↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2021

RASSF1A independence and early Galectin-1 upregulation in PIK3CA induced hepatocarcinogenesis: new therapeutic venues

Aberrant activation of the PI3K/AKT/mTOR and Ras/Mitogen-Activated Protein Kinase pathways is a hepatocarcinogenesis hallmark. In a subset of hepatocellular carcinomas (HCC), PI3K/AKT/mTOR signaling dysregulation depends on PIK3CA mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor RASSF1A. To evaluate a possible co-carcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wildtype mice by hydrodynamic tail vein injection combined with Sleeping Beauty-mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce hepatocellular carcinomas in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of Fatty acid synthase and Stearoyl-CoA desaturase-1 (SCD1). Galectin-1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co-inhibitory treatment with PIK3CA inhibitors and the Galectin-1 inhibitor OTX-008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues. Graphical AbstractHydrodynamic tail vein injection of Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutant forms E545K and H1047R induces stepwise hepatocarcinogenesis in mice, independent of Ras association domain-containing protein 1 (RASSF1A) status. Gene expression analyses revealed an early increase in Galectin-1, which regulates the lipogenic enzyme Stearoyl-CoA desaturase-1 (SCD1). PIK3CA- and Galectin1 inhibitors act synergistically, pointing at novel therapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/448477v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@3e6292org.highwire.dtl.DTLVardef@1b994b5org.highwire.dtl.DTLVardef@d22411org.highwire.dtl.DTLVardef@3e05a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2020

Fascin1 empowers YAP mechanotransduction and promotes cholangiocarcinoma development

Mechanical forces control cell behavior, including cancer progression. Cells sense forces through actomyosin and YAP, but what regulators of actin mechanotransduction play relevant roles in vivo remains unclear. Here we identify the Fascin1 F-actin bundling protein as a key factor sustaining YAP activation in response to ECM mechanical cues. This is relevant in the mouse liver, where Fascin1 regulates YAP-dependent hepatocyte dedifferentiation. Moreover, Fascin1 is required in the AKT/NICD system and sufficient together with AKT to induce cholangiocarcinomas in mice, recapitulating genetic YAP requirements, and its expression in intrahepatic cholangiocarcinomas correlates with aggressiveness and poor patient prognosis. We propose that Fascin1 represents a pro-oncogenic mechanism that can be exploited during intrahepatic cholangiocarcinoma development to overcome a mechanical tumor-suppressive environment.

cancer biology↗