Synthetic Essentiality of Tdo2 In Apc-Mutated Colorectal Cancer

<p>Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is</p> <p>common genetic event across many cancers and serves a critical initiating</p> <p>event in the majority of sporadic colorectal cancers (CRC). The WNT/APC</p> <p>pathway remains an elusive target for cancer, prompting us to explore</p> <p>orthogonal strategies to identify specific vulnerabilities for APC-deficient</p> <p>CRC and other cancers. Using the concept of synthetic essentiality (SE), we</p> <p>sought to identify essential effectors of APC deficiency with the goal of</p> <p>expanding targetable vulnerabilities in CRC. We identified Tryptophan 2,3-</p> <p>dioxygenase 2 (TDO2) as an SE gene for APC-deficient cancers.</p> <p>Mechanistically, APC loss results in TCF4/b-catenin-mediated activation of</p> <p>TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway</p> <p>which boosts glycolysis, promotes proliferation, and upregulates CXCL5</p> <p>which recruits macrophages into the tumor microenvironment (TME). These</p> <p>tumor-associated macrophages not only suppress anti-tumor immunity but</p> <p>serve to support cancer cell survival via their secretion of GAS6 which</p> <p>activates AXL in cancer cells, consistent with heterotypic symbiotic</p> <p>signaling in the TME. Thus, APC-deficiency activates a TCF4-TDO2-AhR-</p> <p>CXCL5-GAS6-AXL circuit that impacts multiple cancer hallmarks via</p> <p>autonomous and non-autonomous mechanisms, and illuminates new</p> <p>therapeutic targets for APC mutant cancers.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2021

Authors dc:creator

• Lee, Rumi
• <p>0000-0002-5732-9179</p>

Contributors dc:contributor

• Ronald DePinho, M.D.
• Guillermina Lozano, Ph.D.
• Scott Kopetz, M.D., Ph.D.

• Colorectal Cancer
• APC
• synthetic essentiality
• TDO2
• Tumor-associated macrophages
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1132

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2190