PhD defence R. (Roberto) Stabile

Brief summary:

This thesis investigates the critical role of epigenetics in regulating phenotypic plasticity in colon and oral cancer. It explores how chromatin remodelers and microRNAs drive cancer progression and metastasis. In colon cancer, the thesis identifies distinct subpopulations of cancer cells, such as EpCAM lo, with heightened motility, invasiveness, and chemotherapy resistance. These findings are linked to the CMS4 subtype, which is associated with poor prognosis. In addition, the study reveals the existence of various subpopulations within the same cancer line, including cancer stem cells, and demonstrates their differing roles in tumor behavior, supported by spatial transcriptomic data from patient-derived tumors.

In oral cancer, the thesis delves into the suppression of the CDK2AP1 tumor suppressor gene. Despite a low mutation frequency, CDK2AP1 is often downregulated due to microRNA interference, impacting patient survival. Further, the work highlights the competitive interplay between the SWI/SNF and NuRD chromatin remodeling complexes and their roles in inflammation and epithelial-mesenchymal plasticity. It shows that loss of CDK2AP1 enhances a pro-inflammatory secretome, driving tumor-associated macrophage recruitment. These findings suggest the potential of CDK2AP1 as a prognostic marker and therapeutic target.

In summary, the thesis emphasizes the pivotal role of epigenetics in regulating phenotypic plasticity and its impact on cancer progression, with implications for novel therapeutic strategies.