Abstract 3481: A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma

Abstract

Tumors exhibit widespread enhancer landscape reprogramming compared to normal tissue. The etiology is believed to be largely cell-intrinsic in non-hormonal cancers, attributed to such genomic alterations as focal amplification of non-coding regions, aberrant activation of transcription factors, and non-coding mutations creating de novo transcription factor binding sites. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon epithelia, we find divergent epigenetic landscapes between primary CRC tumors and CRC cell lines. We identify a unique super-enhancer signature largely absent in cell culture. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over patient-matched normal epithelium suggesting novel insight into the etiology of enhancer reprogramming in CRC and its downstream relevance to tumor biology. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. CRISPR-dcas9-KRAB interference of this super-enhancer identifies PDZK1IP1 as its target gene. PDZK1IP1 is previously observed to be highly up-regulated in CRC. However, the mechanism behind its transcriptional activation is not fully understood. We restore both the super-enhancer and PDZK1IP1 levels following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating its etiology via local tumor microenvironment acquisition. Deletion of inflammatory transcription factors RELA and STAT3 in human CRC cells inhibits PDZK1IP1 induction in xenografts. PDZK1IP1 appears to be critical for CRC growth in the setting of its super-enhancer induction as xenografts, but not in cell culture where the super-enhancer is absent and expression is largely silent. Building on its known role in glucose uptake via SGLT receptors, we demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway using polar metabolomic profiling. We show this activation enables efficient growth under oxidative conditions both in vitro and in vivo, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the biologic significance of epigenomic profiling on patient-matched primary specimens and identify this microenvironment-acquired super-enhancer as an oncogenic driver in the setting of the inflamed tumor. Citation Format: Royce Zhou, Jia Xu, Tiphaine Martin, Alexis Zachem, John He, Sait Ozturk, Deniz Demircioglu, Ankita Bansal, Andrew Trotta, Bruno Giotti, Berkley Gryder, Yao Shen, Saul Carcamo, Xuewei Wu, Kaitlyn Bosch, Benjamin Hopkins, Alexander Tsankov, Randolph Steinhagen, Drew Jones, John Asara, Jerry Chipuk, Rachel Brody, Steven Itzkowitz, Iok In Christine Chio, Dan Hasson, Emily Bernstein, Ramon Parsons. A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3481.