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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE200910 | GEO | 2022/07/13

REPOSITORIES: GEO

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

Project description: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.SignificanceThis 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.

| S-EPMC9262860 | biostudies-literature

Synthetic Essentiality of Tryptophan 2,3-dioxygenase 2 in APC-Mutated Colorectal Cancer [array]

Project description:We examined the pathways that are regulated by TDO2 in APC-deficient cancer cells by analyzing gene expression profiles of APC-WT and APC-KO MC38 cells that are transduced with inducible shTDO2 constructs. This study establishs that the TDO2-Kyn-AhR axis serves a critical role in promoting APC-deficient tumor growth via cancer cell autonomous (metabolism and proliferation) and non-autonomous mechanisms (tumor immunity).

2022-07-13 | GSE201415 | GEO

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

Project description:Comparative transcriptomic analysis of TAMs isolated from APC-WT and APC-KO MC38 orthotopic tumors express higher levels of multiple classical M2-like markers (CD163, CCL22, YM1) compared to APC-WT tumors after re-normalized the read counts of multiple M2 macrophage markers with housekeeping gene read counts (GAPDH and ACTB).

2022-07-13 | GSE200909 | GEO

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

2022-07-13 | GSE200908 | GEO