Targeting cholesterol metabolism for the treatment of serrated colorectal tumors

Hard-to-detect colorectal precancerous lesions known as serrated polyps and the aggressive tumors that develop from them are linked to increased production of cholesterol, according to preclinical studies by Weill Cornell Medicine researchers. It depends a lot. This finding points to the possibility of using cholesterol-lowering drugs to prevent or treat such tumors.

In a study published on October 13, nature communicationsThe researchers analyzed mice that developed serrated polyps and tumors and detailed the cascade of molecular events in these tissues that lead to increased cholesterol production.

They confirmed their findings in an analysis of human serrated polyps and tumors, and showed that inhibiting cholesterol production halted the progression of these types of intestinal tumors in a mouse model that replicated human cancers. Indicated.

Serrated-type polyps and tumors are not currently treated differently than other colorectal tumors, but as our study shows, they have unique metabolic vulnerabilities that can be targeted. ”

Dr. Jorge Moscat, co-senior author of the study, Homer T. Hearst III Professor of Pathology and Oncology, vice chair of Cellular and Cancer Pathobiology in the Department of Pathology and Laboratory Medicine, and member of the Sandra Edward Meyer Cancer Center Weill・At Cornell Medical College

The other co-senior author is Dr. Maria Diaz Meco, also the Homer T. Hearst III Professor of Pathological Oncology and a member of the Meyer Cancer Center at Weill Cornell Medicine. The study’s lead author is Dr. Yu Muta, a postdoctoral fellow in the Moscat/Diaz-Meco lab.

Cholesterol is generally considered to be a growth-promoting molecule that is a component of cell membranes and has other growth-supporting functions. Previous studies have shown a link between high blood cholesterol levels and various cancers, including colorectal cancer. However, it is not clear whether lowering cholesterol, for example using common statin drugs, can prevent colorectal cancer.

“Clinical trials of statins to prevent colorectal cancer have yielded conflicting results,” said Dr. Díaz-Meco. “Our findings suggest that targeting cholesterol may have a preventive but selective effect only on this serrated type of polyp or tumor.”

Serrated polyps are so called because they look serrated under a microscope. Because they are flatter than regular colorectal polyps, they are often missed during colonoscopies. However, the tumors in which they arise, which account for approximately 15 to 30 percent of colorectal cancers, contain many “metaplastic” cells that are particularly invasive and resistant to treatment.

Several years ago, the Moscat/Diaz-Meco team linked serrated polyps and tumors to low levels of two enzymes known as aPKC. They showed that mice engineered to lack these aPKC enzymes in their intestinal lining reliably form serrated polyps and subsequently aggressive tumors.

In a new study, scientists found that cholesterol synthesis was significantly upregulated in the serrated tumors of these mice, and even in the intestinal tissue primed for the development of these types of cancerous lesions. , suggesting that cholesterol may be an early driver of tumor development.

Researchers have shown how the absence of the aPKC enzyme, particularly in metaplastic tumor cells, triggers the activation of a transcription factor called SREBP2 that switches on cholesterol production. Examination of colorectal polyp and tumor samples taken from human patients was consistent with the findings in mice. They found, for example, that only serrated tumors had lower aPKC levels, with accumulation of SREBP2, a driver and marker for upregulation of cholesterol biosynthesis in serrated cancer cells.

Finally, the researchers tested a combination of two cholesterol synthesis inhibitors, including the widely used atorvastatin. This treatment, given when low-aPKC mice were still very young, significantly reduced the rate at which both serrated polyps and tumors formed later on, and the serrated-type tumors that did form were significantly less likely to form in untreated mice. It was less invasive than what normally occurs in .

This result indicates that targeting cholesterol may be an effective strategy for the treatment and prevention of serrated colorectal tumors. The Moscato Institute and the Diaz-Meco Institute now hope to launch an early clinical trial of a cholesterol-lowering intervention in patients who have had serrated colorectal polyps removed.

“Currently, these polyps are removed when they are caught early during a colonoscopy, and patients can only hope that they do not come back,” Dr. Moscato said. “In the future, we hope to develop more aggressive ways to prevent this highly aggressive cancer before it progresses completely and becomes difficult to treat.”