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

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

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

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

Loss of adenomatous polyposis coli (APC) is considered a critical initiating event in colorectal cancer (CRC), where it occurs in 90% of sporadic CRCs. APC deficiency results in activation of WNT; however, major hurdles persist to therapeutic intervention of this pathway. Here, the synthetic essentiality framework was used to discover other potential druggable vulnerabilities for APC-deficient cancers. Through this approach, tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient CRC. Upregulation of TDO2 activates the Kyn-AhR pathway, increasing glycolysis. Subsequent cancer cell growth and CXCL5 secretion leads to macrophage recruitment into the tumor microenvironment. APC-deficient CRC models were found to be susceptible to both TDO2 depletion and pharmacologic inhibition. Overall, this study identifies the TCF4-TDO2-AhR-CXCL5 axis as a critical pathway in the maintenance of APC-deficient CRC, informing potential genotype-specific therapeutic targets and the use of TDO2 inhibitors to combat this disease. Citation Format: 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. Synthetic essentiality identifies TDO2 as a key target in APC-deficient CRC [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA014.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Excessive activation of the ionotropic N-methyl-D-aspartate (NMDA) receptor has been shown to cause abnormally high levels of Ca

Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo. In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer. Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823–33. ©2018 AACR.

Post-transcriptional gene regulation is an important step in eukaryotic gene expression. The last step to govern production of nascent peptides is during the process of mRNA translation. mRNA translation is controlled by many translation initiation factors that are susceptible to post-translational modifications. Here we report that one of the translation initiation factors, eIF4E, is phosphorylated by Mammalian Ste20-like kinase (MST1). Upon phosphorylation, eIF4E weakly interacts with the 5' CAP to inhibit mRNA translation. Simultaneously, active polyribosome is more associated with long noncoding RNAs (lncRNAs). Moreover, the linc00689-derived micropeptide, STORM (Stress- and TNF-α-activated ORF Micropeptide), is triggered by TNF-α-induced and MST1-mediated eIF4E phosphorylation, which exhibits molecular mimicry of SRP19 and, thus, competes for 7SL RNA. Our findings have uncovered a novel function of MST1 in mRNA and lncRNA translation by direct phosphorylation of eIF4E. This novel signaling pathway will provide new platforms for regulation of mRNA translation via post-translational protein modification.