Project no. : uniri-Biomed-18-76 Molecular features associated with BRAFV600E-mutated versus wild type BRAF colorectal cancer
This research project represents an upgrade to the CSF project No. 2018-01 3900 Dissecting the mechanisms of therapy resistance in BRAF-mutant colon cancer using an integrated omics approach. The CSF project will illuminate processes underlying the development of resistance to BRAF inhibition by vemurafenib in BRAFV600E mutant colorectal cancer (CRC) cells via integration of results of the proteome, glycoproteome, secretome and sphingolipidome analysis. The CSF project will identify novel biomarkers and targets associated with the development of resistance to vemurafenib in BRAF mutant CRC cells and will investigate the role of bioactive sphingolipid metabolism in acquired resistance to vemurafenib.
However, identification of molecular and cellular mechanisms specifically modulated by oncogenic BRAF mutation represents an important piece of information that adds to a better understanding of the role of BRAFV600E mutant protein in the regulation of growth, survival and response of CRC cells to chemotherapy. This project has several goals: 1. explore differences in the molecular profiles (global proteome, sphingoid bases) between BRAF mutant vs. wild-type BRAF CRC cells to identify molecular factors associated with the aggressive phenotype of BRAF mutant CRC; 2. determine the correlation between BRAF status and the expression of the key proteins regulating metabolism and functions of bioactive sphingolipids; 3. identify proteins at the level of global proteome and the key enzymes in sphingolipid metabolism and signaling whose expression is directly controlled by BRAF mutant protein. Results obtained in this study are expected to reveal new molecular features of the aggressive phenotype of BRAFV600E mutant CRC, whose validation in tissues from CRC patients will deliver novel histopathologic biomarkers as a foundation for the development of new diagnostic and prognostic tools.