TY - JOUR
T1 - A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma
AU - Zhou, Royce W.
AU - Xu, Jia
AU - Martin, Tiphaine C.
AU - Zachem, Alexis L.
AU - He, John
AU - Ozturk, Sait
AU - Demircioglu, Deniz
AU - Bansal, Ankita
AU - Trotta, Andrew P.
AU - Giotti, Bruno
AU - Gryder, Berkley
AU - Shen, Yao
AU - Wu, Xuewei
AU - Carcamo, Saul
AU - Bosch, Kaitlyn
AU - Hopkins, Benjamin
AU - Tsankov, Alexander
AU - Steinhagen, Randolph
AU - Jones, Drew R.
AU - Asara, John
AU - Chipuk, Jerry E.
AU - Brody, Rachel
AU - Itzkowitz, Steven
AU - Chio, Iok In Christine
AU - Hasson, Dan
AU - Bernstein, Emily
AU - Parsons, Ramon E.
N1 - Funding Information:
We thank members of the Ramon Parsons Laboratory, Bert Vogelstein, Matthew Vander Heiden, and Lewis Cantley for discussions. We thank Saboor Hekmaty, Kevin Mohammed, and Ravi Sachidanandam from the Mount Sinai Oncological Sciences Sequencing Core Facility. We thank the Division of Colon and Rectal Surgery at Mount Sinai and Dr. Rachel Brody at the TCI Biorepository Core in Development for their assistance with sample collection. This study was supported by the following: National Institutes of Health grant F30CA243207 to R.W.Z., R35CA220491 to R.E.P., R01CA230854 to R.E.P., P30CA196521 to R.E.P, R01CA154683 to E.B., and R01CA218024 to E.B.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over normal. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating cell-extrinsic etiology. We demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway. We show this activation enables efficient growth under oxidative conditions, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the significance of epigenomic profiling on primary specimens.
AB - Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over normal. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating cell-extrinsic etiology. We demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway. We show this activation enables efficient growth under oxidative conditions, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the significance of epigenomic profiling on primary specimens.
UR - http://www.scopus.com/inward/record.url?scp=85139864767&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-33377-8
DO - 10.1038/s41467-022-33377-8
M3 - Article
AN - SCOPUS:85139864767
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 6041
ER -