Scientists at Cold Spring Harbor Laboratory have found that they can stop the growth of pancreatic cancer cells by interfering with the way the cells store cholesterol. Their findings, published today in the Journal of Experimental Medicine, point toward a new treatment strategy.
David Tuveson and his team wanted to know why pancreatic cancer cells, like many cancer cells, manufacture abundant amounts of cholesterol. Cholesterol is an essential component of cell membranes, but the research team determined that pancreatic cancer cells make far more of it than they need to support their own growth.
Most cells make only as much cholesterol as they need, quickly shutting down the synthesis pathway once they have enough, says Tobiloba Oni, a graduate student in Tuveson's lab. But the team found that cancer cells convert most of the cholesterol they make into a form that can be stored within the cell. Free cholesterol never accumulates, and the synthesis pathway keeps churning out more.
Cancer cells in the pancreas seem to thrive off this hyperactive cholesterol synthesis. The team thinks this is probably because they are taking advantage of other molecules generated by the same pathway. They're able to keep the pathway running and maintain their supply thanks to sterol O-acyltransferase 1 (SOAT1), which converts free cholesterol to its stored form and which pancreatic cancer cells have in abundance.
When the researchers eliminated the SOAT1 enzyme through genetic manipulation, preventing cells from converting and storing their cholesterol, cancer cells stopped proliferating. In animal experiments, eliminating the enzyme stalled tumor growth.
Importantly, the team found that eliminating SOAT1 only impacted cells that harbored mutations in both copies of p53. This genetic alteration promotes cancer growth and is exceedingly common in patient tumors. Normal pancreas cells functioned just fine without the enzyme in the team's experiments, which positions SOAT1 as a promising therapeutic target.