Scientists at the Mount Sinai Tisch Cancer Institute say they have identified a new gene that is essential to colon cancer growth and found that inflammation in the external environment around the tumor can contribute to the growth of tumor cells. The team published its study “A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma” in Nature Communications.
This is reportedly the first time that researchers have discovered that the environment around a colon cancer tumor can program what is known as a “super enhancer,” a complex area of DNA with a high concentration of transcriptional machinery that controls whether a cell is malignant. This super enhancer regulates the gene PDZK1IP1, which was previously not identified as a cancer gene. Once deleted PDZK1IP1 was deleted, colon cancer growth slowed down, suggesting that PDZK1IP1 and its super enhancer could be targets for anti-cancer therapies.
“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,” write the investigators.
“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.”
Third most prevalent and second most deadly cancer in the U.S.
“In the United States, colon cancer is the third most prevalent and second most deadly cancer,” said the study’s first author Royce Zhou, an MD/PhD student at the Icahn School of Medicine at Mount Sinai. “This cancer is reliant on surgery for treatment, and immunotherapies that have revolutionized the treatment of advanced cancer have only worked for a small subset of colon cancer patients. That’s why there’s a great need for novel target identification.”
This study found that the super enhancer is activated by surrounding inflammation in the tumor microenvironment. The inflammation allows the cancer cells to survive in an environment they otherwise would not. Inflammatory bowel disease is a known risk for colon cancer; this finding could add to the understanding of the mechanism involved.
“What this means for most patients with colon cancer is that inflammation that’s occurring in the tumor is contributing to the tumor’s growth. This stresses the importance of understanding what we can do to curb the inflammatory effects in the colon through prevention or understanding what dietary effects might have on the microenvironment in the colon,” noted senior author Ramon Parsons, MD, PhD, director of the Tisch Cancer Institute. “In terms of treatment, we have genetic evidence that targeting this gene actually inhibits tumors. By understanding all these different components, we will have better tools to try to prevent the disease.”
This discovery was made possible by studying live tumor tissue and surrounding healthy tissue immediately after the surgeries of 15 colon cancer patients. Being able to prepare and analyze live cells allowed researchers to see the tumor microenvironment and the genetic and biologic drivers of colon cancer, pointed out Zhou.
“We had live specimen live cells straight from the operating room that allowed us to immediately measure the epigenetic state of that tumor,” Parsons added.
