Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2022 Jul 6;12(7):1702-1717. doi: 10.1158/2159-8290.CD-21-0680.
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.
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.
腺瘤性结肠息肉病（APC）失活在许多癌症类型中都很常见，是大多数散发性结直肠癌中关键的起始事件。APC 缺陷激活 WNT 信号通路，这仍然是癌症治疗的一个难以捉摸的靶点，促使我们应用合成必需性框架来确定 APC 缺陷癌症的可用药弱点。色氨酸 2,3-双加氧酶 2（TDO2）被鉴定为 APC 缺陷结直肠癌的合成必需效应因子。从机制上讲，APC 缺陷导致 TCF4/β-连环蛋白介导的 TDO2 基因转录上调。TDO2 反过来激活 Kyn-AhR 通路，增加糖酵解以驱动合成代谢癌细胞生长，并分泌 CXCL5 将巨噬细胞招募到肿瘤微环境中。在治疗上，APC 缺陷结直肠癌模型易受 TDO2 耗竭或药物抑制的影响，这会损害癌细胞增殖并增强抗肿瘤免疫特征。因此，APC 缺陷激活了 TCF4-TDO2-AhR-CXCL5 回路，通过自主和非自主机制影响多种癌症特征，并阐明了结直肠癌中的特定基因型弱点。
本研究鉴定了维持 APC 缺陷结直肠癌的关键效应因子，并证明了 APC/WNT 通路与犬尿氨酸通路信号之间的关系。它进一步确定了 APC 缺陷结直肠癌中的肿瘤相关巨噬细胞生物学，为特定基因型的治疗靶点和 TDO2 抑制剂的使用提供了信息。本文在本期特色文章中得到了强调，第 1599 页。
