Author ORCID Identifier

0000-0002-5732-9179

Date of Graduation

8-2021

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Ronald DePinho, M.D.

Committee Member

Guillermina Lozano, Ph.D.

Committee Member

Scott Kopetz, M.D., Ph.D.

Committee Member

Glen Traver Hart, Ph.D.

Committee Member

Y. Alan Wang, Ph.D.

Abstract

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.

Keywords

Colorectal Cancer, APC, synthetic essentiality, TDO2, Tumor-associated macrophages

Available for download on Saturday, August 06, 2022

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