IDENTIFICATION OF CHROMATIN MODIFYING ENZYMES ASSOCIATED WITH COLON CANCER AGGRESSIVE PROPERTIES

One of the challenges of colon cancer treatment is to eradicate cells that are responsible for relapse and metastasis. Epigenetic mechanisms per se (DNA methylation and histone post-translational modifications) play a major role in orchestrating the phenotypic and functional properties of colonic epithelial cells throughout life and during carcinogenesis. The expression of complete partitions of tumor suppressor genes or oncogenes, among others, depends on chromatin-modifying enzyme complexes (epienzymes) and can be dynamically activated or inhibited to promote a large range of aggressive properties of cancer cells (tumor progression, plasticity, resistance to conventional and targeted therapies, metastasis). However, to date, the use and efficacy of epigenetic inhibitors (epidrugs) as therapies for solid tumors remain limited due to a lack of target specificity and insufficient consideration of intra-tumoral and inter-individual heterogeneity. Better identification of the epigenetic regulators involved in these key tumor processes would enable to refine the use of epigenetic therapies or to propose new strategies. We hypothesized that dynamic combinations of epienzymes are responsible for the aggressive phenotype of digestive cancer cells. Our objectives were to:•Set up in vitro models to capture the dynamic nature of epigenetic mechanisms involved in chemoresistance,•Study the role of two modulators of histone 3 lysine 9 trimethylation (an inactive epigenetic mark), the transcriptional corepressor PRDM1 and the lysine demethylase KDM4B, whose expression had previously been shown in the laboratory to be associated with markers of aggressive properties in colon and pancreatic cancers,•Identify an epienzyme signature associated with poor prognosis and aggressive molecular subtypes in patients with colon cancer.This thesis work allowed us to:•Propose new patient-derived tumor organoid models (PDTO) and colon cancer cell lines exposed to conventional combinations of chemotherapies (FOLFIRINOX and FOLFOX regimens) used in digestive cancers,•Validate the functional role of KDM4B and PRDM1 in several facets of tumor aggressive properties, including (i) their heterogeneous and dynamic expression profile during chronic exposure to chemotherapy, (ii) the binding profile of KDM4B at promoters of genes involved in proliferation and stemness using CUT&RUN, and (iii) the impact of their inhibition on proliferation, chemosensitivity and tumorigenicity in vitro and in vivo,•Identify epienzymes associated with colon cancer patient survival (through analysis of public databases) and intra-tumoral heterogeneity (through analysis of spatial transcriptomics data obtained during this thesis work).Overall, our work has shown that the specific expression of chromatin-modifying enzymes is a key step in the acquisition of resistance to conventional therapies. Specific targeting of the protein complexes in which these epienzymes are engaged through a strategy of protein-protein interaction inhibition could pave the way for new therapeutics. The efficacy of these 3rd-generation inhibitors could be far superior compared to existing epidrugs, which target the catalytic sites of entire families of chromatin modifiers and enable circumventing the aggressive properties of digestive cancer cells.