Role of RAF1 in colorectal carcinogenesis in 3D models

Colorectal cancer (CRC) is the third most common cancer and one of the leading causes of cancer- related deaths world-wide. Even if surgery and chemotherapeutic treatments are constantly in progress, cancer relapse remains frequent and around 50% of patients die within five years following the initial diagnosis. Therefore, understanding the molecular mechanisms behind its development and progression is essential for the design of new therapies. Mutations in KRAS gene occur in approximately 40% of CRC and induce deregulation of several biological processes, leading to cancer development and progression. Importantly, tumors with a KRAS mutation are refractory to some anti- cancer therapies commonly used in CRC treatment. Downstream of mutated KRAS, a protein called RAF1 exerts specific functions, controlling for instance cell migration, which is important for metastasis development. Several lines of evidence suggest potential roles of RAF1 in CRC, but the underlying mechanisms remains unclear. In this project, we propose to investigate the role of RAF1 in colorectal carcinogenesis using in vitro models mimicking the in vivo tumors. We will study the impact of RAF1 loss on different biological processes in CRC with different genetic backgrounds and use a targeted and unbiased approaches to identify the direct targets of RAF1 which play a role in cancer progression, as well as potential new targets specific of CRC carcinogenesis. From a clinical point of view, it is hoped that the results obtained in this project could be exploited for the design of new therapies for this disease.