Synthetic Essentiality of Tryptophan 2,3-Dioxygenase 2 in APC-Mutated Colorectal Cancer

Authors

Rumi Lee
Jiexi Li
Jun Li
Chang-Jiun Wu
Shan Jiang
Wen-Hao Hsu
Deepavali Chakravarti
Peiwen Chen
Kyle A LaBella
Jing Li
Denise J Spring
Di Zhao
Y Alan Wang
Ronald A DePinho

Publication Date

7-6-2022

Journal

Cancer Discovery

Abstract

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient colorectal cancer models were susceptible to TDO2 depletion or pharmacologic inhibition, which impaired cancer cell proliferation and enhanced antitumor immune profiles. Thus, APC deficiency activates a TCF4-TDO2-AhR-CXCL5 circuit that affects multiple cancer hallmarks via autonomous and nonautonomous mechanisms and illuminates a genotype-specific vulnerability in colorectal cancer.

Significance: This study identifies critical effectors in the maintenance of APC-deficient colorectal cancer and demonstrates the relationship between APC/WNT pathway and kynurenine pathway signaling. It further determines the tumor-associated macrophage biology in APC-deficient colorectal cancer, informing genotype-specific therapeutic targets and the use of TDO2 inhibitors. This article is highlighted in the In This Issue feature, p. 1599.

Keywords

Adenomatous Polyposis Coli, Colorectal Neoplasms, Dioxygenases, Humans, Tryptophan, Tryptophan Oxygenase, Tumor Microenvironment, Wnt Signaling Pathway, beta Catenin, APC, TDO2, CXCL5, Tumor-associated macrophages, Colorectal cancer

DOI

10.1158/2159-8290.CD-21-0680

PMID

35537038

PMCID

PMC9262860

PubMedCentral® Posted Date

1-6-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes