Biology subjects

Randic, T.

Publications and source records attributed to Randic, T..

3 recordsLinked to original sources

bioRxiv2025

UHRF1 Overexpression Generates Distinct Senescent States with Different Tp53 Dependencies

SummarySenescence is a pleiotropic phenotype that alternatively suppresses or promotes cancer. The tumor suppressive roles are linked to clearance of damaged cells by the immune system, while cells with tumor promoting functions resist apoptosis, evade immune clearance and either persist and support the tumor microenvironment, or escape and proliferate. What generates these diverse populations is unclear. We investigated this in preneoplastic zebrafish livers where the epigenetic regulator, UHRF1, is overexpressed in hepatocytes. Double strand breaks, DNA methylation repatterning, retrotransposon expression, cell cycle withdrawal and activation of Atm and Tp53 dependent senescence were early responses to UHRF1 overexpression. This evolved to generate diverse populations of senescent cells, some which expressed immune and senescence signatures plus anti-apoptotic markers, and others co-expressed proliferative genes. The fate of these populations was dictated by UHRF1 levels and Tp53, as Tp53 loss enabled proliferation of cells with reduced UHRF1 expression but not in cells expressing high UHRF1. The senolytic Navitoclax targeted only a subset of senescent cells. Thus, the diversity of senescent cells driven by epigenetic changes can generate divergent outcomes. Short summaryUHRF1 overexpression in zebrafish hepatocytes induces DNA damage leading to Atm-tp53-dependent senescence with UHRF1 levels dictating whether hepatocytes remain senescent, escape, or undergo senolytic elimination.

cancer biology↗

bioRxiv2024

Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity

Tumor heterogeneity is the substrate for tumor evolution and the linchpin of treatment resistance. Cancer cell heterogeneity is largely attributed to distinct genetic changes within each cell population. However, the widespread epigenome repatterning that characterizes most cancers is also highly heterogenous within tumors and could generate cells with diverse identities and malignant features. We show that high levels of the epigenetic regulator and oncogene, UHRF1, in zebrafish hepatocytes rapidly induced methylome disordering, loss of heterochromatin, and DNA damage, resulting in cell cycle arrest, senescence, and acquisition of stemness. Reducing UHRF1 expression transitions these cells from senescent to proliferation-competent. The expansion of these damaged cells results in hepatocellular carcinomas (HCC) that have immature cancer cells intermingled with fibroblasts, immune and senescent cells expressing high UHRF1 levels, which serve as reservoirs for new cancer cells. This defines a distinct and heterogenous HCC subtype resulting from epigenetic changes, stemness and senescence escape.

cancer biology↗

bioRxiv2023

A multi-omics integrative approach unravels novel genes and pathways associated with senescence escape after targeted therapy in NRAS mutant melanoma

Therapy Induced Senescence (TIS) leads to sustained growth arrest of cancer cells. The associated cytostasis has been shown to be reversible and cells escaping senescence further enhance the aggressiveness of cancers. Together with targeted therapeutics, senolytics, specifically targeting senescent cancer cells, constitute a promising avenue for improved cancer treatments. Understanding how cancer cells evade senescence is needed to optimise the clinical benefits of this therapeutic approach. Here we characterised the response of three different NRAS mutant melanoma cell lines to a combination of CDK4/6 and MEK inhibitors over 33 days. Transcriptomic data show that all cell lines trigger a senescence programme coupled with strong induction of interferons. Kinome profiling revealed the activation of Receptor Tyrosine Kinases (RTKs) and enriched downstream signaling of neurotrophin, ErbB and insulin pathways. Characterisation of the miRNA interactome associates miR-211-5p with resistant phenotypes. Finally, iCELL-based integration of bulk and single-cell RNA-seq data identified biological processes perturbed during senescence, and predicts new genes involved in its escape. Overall, our data associate insulin signaling with persistence of a senescent phenotype and suggest a new role for interferon gamma in senescence escape through the induction of EMT and the activation of ERK5 signaling.

cancer biology↗