Abstract
More than 95% of patients diagnosed with an invasive colorectal cancer (CRC) die within 5 years, mainly due to the metastatic spread of the disease. Therefore, a better understanding of signaling pathways promoting metastatic progression is warranted to identify novel therapeutic strategies in this cancer. The tyrosine kinase and signaling protein SRC has emerged as an important determinant of this metastatic process. SRC deregulation induces intestinal cancer stem cell proliferation and dissemination and is a marker of poor prognosis in CRC patients. However, the way how SRC promotes cancer invasion remains unclear because SRC is rarely mutated in human cancer. Interestingly, my host lab identified an important mechanism in the control of SRC tumor activity via the anti-oncogenic function of the small adaptor protein SLAP in CRC. Mechanistically, SLAP promotes ubiquitination-dependent degradation of critical substrates, such as the adhesive receptor EphA2, to dampen SRC oncogenic signaling. Interestingly, by proteomics, I discovered an additional mechanism underlying anti-oncogenic activity, which involves the serine/threonine kinase and metastasis inducer mTORC2. My results show that mTORC2 is an additional target of SLAP in CRC cells and that SLAP inhibits mTORC2 signaling to exert its inhibitory effect on CRC cells. Mechanistically, SLAP inhibits mTORC2 signaling by promoting the complex’s disassembly via the targeting of the regulatory subunit LST8. Finally, I showed that the level of SLAP dictates the tumor response to mTOR catalytic inhibitors in CRC cells. Collectively, these data support an additional important mechanism by which SLAP controls tumor activity and unveil SLAP as a potential biomarker of response to catalytic mTOR inhibitors in CRC.