Characterizing the Role of the RET Receptor Tyrosine Kinase in Colorectal Cancer
RET is a receptor tyrosine kinase (RTK) that plays important roles in both normal development and cancer. RET has well-established oncogenic roles in thyroid cancer and growing evidence implicates RET activity in the development and progression of other tumor types, including pancreatic and breast cancer. RET is activated by interacting with its ligand, a member of the GDNF family, and a co-receptor, a member of the GFRα family. This tri-molecular complex activates RET-mediated downstream signaling pathways which promote a variety of cellular processes, including proliferation, migration, and survival. RTK-mediated activation of these pathways is an established method of colorectal cancer (CRC) development and progression to a metastatic phenotype. RET expression has been identified in CRC, however its role in this disease remains unclear. Here, we investigated the effects of RET activity in CRC. We first developed a novel in vitro method for generating and using 3D cell spheroids as a more physiologically representative assessment of cell behaviour compared to traditional 2D methodologies. We subsequently used this model in our study of RET-mediated CRC progression. We showed that RET activity in CRC cells promotes a more mesenchymal-like phenotype, and enhances cell proliferation, migration, and 3D invasion. We also assessed RET expression in two CRC patient cohorts. RET expression was correlated with malignancy and poor patient prognosis. Together, our data suggest an oncogenic role for RET in CRC which may be of future interest as a potential therapeutic target.