Biology subjects

Richart, L.

Publications and source records attributed to Richart, L..

3 recordsLinked to original sources

bioRxiv2024

Persister cancer cells are characterized by H4K20me3 heterochromatin that defines a low inflammatory profile

Anti-cancer therapies may induce proliferative arrest in cancer cells in the form of senescence or drug-tolerant persistency, the latter being a reversible arrest with similarities to embryonic diapause. Here, we use mTOR/PI3K inhibition to develop and characterize a model of persistency/diapause-like arrest in human cancer cells of various origins. We show that persister and senescent cancer cells share an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells do not exhibit other features of senescence, such as the loss of Lamin B1, senescence-associated b-galactosidase activity, and an inflammatory phenotype. Compared to senescent cells, persister cells have a profoundly diminished senescence-associated secretory phenotype (SASP), low activation of interferon signaling pathways and lack upregulation of MHC-I presentation. Based on a genome-wide CRISPR/Cas9 screen performed in diapause mouse embryonic stem cells (mESC), we discover that persister human cancer cells are hypersensitive to the inhibition of one-carbon metabolism. This finding led us to uncover that the repressive heterochromatic mark H4K20me3 is enriched at promoters of SASP and interferon response genes in persister cells, but not in senescent cells. Collectively, we define novel features and vulnerabilities of persister cancer cells and we provide insight into the epigenetic mechanisms underlying their low inflammatory and immunogenic activity.

cancer biology↗

bioRxiv2023

EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition

Mutations in chromatin regulators or their histone substrates are widespread in cancer and often play decisive roles in tumorigenesis. These include Polycomb Repressive Complex 2 (PRC2), a histone H3 lysine 27 methyltransferase that shows distinct alterations in each of a range of tumor types. Mechanistically, this tumor-type specificity is poorly understood. Here, we model several of these alterations in a single isogenic system in order to reveal their comparative impacts on chromatin and transcription. Focusing then on gain-of-function substitutions in catalytic subunit EZH2, which occur in [~]25% of follicular lymphomas, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, and that these are alleviated by partial PRC2 inhibition. Ezh2Y641F also causes gains in existing H3K27 acetylation peaks and extensive gene expression changes. Remarkably, Ezh2Y641F transforms the transcriptomic response to PRC2 inhibition, leading notably to the induction of antigen presentation genes in mutant cells. Using a unique longitudinal cohort of FL patient samples we further strengthen the link between EZH2 mutation status and abnormal H3K27 methylation. This analysis also uncovered unexpected variability in the mutational landscape of successive biopsies from the same patient that points to the frequent co-existence of different clones. On a clinical level, this urges caution when stratifying patients based on single tumor sampling. Altogether, our results provide a mechanistic foundation for understanding how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

cancer biology↗

bioRxiv2020

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

cancer biology↗