Abstract PR02: Epigenetic and molecular drivers of inflammation-driven colorectal cancer

Abstract

Abstract Colorectal tumors arise from intestinal epithelial cells in a multistep process that extends over several years resulting in progression from a normal mucosa to invasive carcinoma. Approximately 5% of all CRC are due to inherited genetic mutations (sporadic CRC) while 95% of the cases originate from a state of chronic inflammation, such as observed in CRC arising in patients with inflammatory bowel diseases (IBD-CRC) or with primary sclerosing cholangitis (PSC-CRC). About 70-75% of PSC patients have ulcerative colitis (UC, a form of IBD) and thus PSC-IBD is very similar to IBD-CRC. It is now established that the persistent pro-inflammatory environment that exists in patients with IBD or PSC can trigger molecular changes leading to tumor development. In this study, we have explored the origins of abnormal chronic intestinal inflammation, what sustains it and how it promotes CRC if uncontrolled. Furthermore, we can eliminate intestinal inflammation and prevent invasive carcinoma in a mouse model of chronic inflammation driven malignancy using the azoxymethane [AOM]/dextran sodium sulphate [DSS] model. In this model, DSS injures the colonic mucosa and in repeated chronic cycles promotes inflammation-induced carcinogenesis, which is accelerated by an initial exposure to the pro-carcinogen AOM. The tumor-suppressor protein, Ras association domain family 1A, (RASSF1A or 1A) is epigenetically silenced in numerous cancers, including CRC. 1A can negatively regulate NFκB and intestinal inflammation and its loss triggered acute colitis in a rodent model for IBD. In this study, we utilized mouse models, cell biology, patient samples and 3D intestinal organoids to demonstrate epigenetic silencing of 1A in IBD, PSC and CRC patients and detrimental effects of the expression loss of 1A during chronic inflammation-injury in the AOM/DSS model of IBD-CRC. Loss of 1A resulted in the appearance of colonic hyperplasia and invasive carcinoma. The timing of expression loss of 1A resulted in the hyperactivation of the nucleotide-binding oligomerization domain-containing protein2 (NOD2)/receptor interacting protein kinase 2 (RIPK2) pathway and Yes associated protein (YAP) dependent transcriptional activity. Abnormal phosphotyrosine (pY) activities of both RIPK2 and YAP contributed to the appearance of invasive carcinoma. YAP, when tyrosine phosphorylated, is a transcriptional co-activator of p73-driven cell death and TEAD/RUNX2/SMAD2 driven proliferation, whereas tyrosine phosphorylated RIPK2 can promote the activation of NFkB, the autophagic response and contribute to enhance growth and metastasis. Both RIPK2 and YAP maintain the chronic inflammation state and can drive colonic malignancy and the appearance of CRC. Furthermore, we validated the importance of both pY-YAP and pY-RIPK2 in IBD patient FFPE sections as well as in 3 case study IBD-CRC patients, utilized a small molecule anti-inflammatory to inhibit in vivo chronic inflammation and prevent invasive carcinoma. Both YAP and RIPK2 are novel biomarkers of inflammation-driven CRC and expression loss of RASSF1A may be an early marker for molecular changes during chronic inflammation that may predict the progression to CRC. This abstract is also being presented as Poster A01. Citation Format: Marilyn Gordon, Mohamed Salla, Ahmed Said, Volodko Natalia, Levinus Dieleman, Shariaz Baksh. Epigenetic and molecular drivers of inflammation-driven colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr PR02.