TETCOLON SIGNED

Project "TETCOLON" data sheet

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 Project objective

Colorectal cancer (CRC) results from the accumulation of genetic and epigenetic changes in colonic epithelial cells. Epigenome studies revealed that virtually all CRCs contain aberrantly methylated genes and perturbed methylation patterns. Ten-Eleven Translocation (TET) protein family dioxygenases oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further to other oxidized 5mCs, supporting active DNA demethylation and helping maintain epigenomic stability. Loss of TET1 is an oncogenic driver in some CRCs. My preliminary analysis indicates that human CRCs have low TET2 mRNA levels compared to normal colorectal tissue, and suggests that low TET2 expression predicts increased mutational load and reduced overall survival. However, whether TET2 deficiency contributes to CRC pathogenesis, or represents a bystander event, remains to be established. In this proposal, I will elucidate the role of TET2 in CRC pathogenesis by testing whether TET2 knockdown induces methylome and transcriptome reprogramming, ultimately promoting (epi)genomic instability and tumor growth. I will also investigate correlations between TET2 defects and molecular/clinico-pathological parameters, and probe TET2 expression as predictive biomarker of response to CRC therapies. With these aims, I will use a multi-disciplinary approach, combining cell biology, cancer epigenetics, bioinformatics, human and mouse studies with cutting-edge techniques such as 3D cell culture and RNA-seq. This study should establish a clear causal link between TET2 loss and CRC pathogenesis, providing new insight into the mechanism of TET2-mediated tumor suppression and leading to the development of innovative therapies that exploit vulnerabilities of TET2-deficient CRC cells. Overall, this project has both basic and translational significance, and the potential to advance our understanding of CRC carcinogenesis and therapeutic response.