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