Blocking cholesterol storage halts pancreatic cancer growth
Scientists identified a novel, highly specific drug target in the enzyme (sterol O-acyltransferase 1 (SOAT1)) cancer cells use to store cholesterol.
Researchers reveal they stopped the growth of pancreatic ductal adenocarcinoma (PDAC) in murine pancreas and whole-animal models by preventing the cells storing cholesterol. They identified that blocking the sterol O-acyltransferase 1 (SOAT1) enzyme specifically prevented cancer cell growth, without impacting healthy cells.
Pancreatic cancer is one of the most common treatment-refractory cancers, with one of the lowest rates of five-year survival. This is primarily due to symptoms of this cancer appearing only once it has spread further through the body rather than when the condition is most treatable. While treatments such as surgery, chemotherapy and radiation therapy (or a combination of the three) may be an option, a novel, more specific pharmaceutical treatment option is highly desirable.
In a paper published in the Journal of Experimental Medicine, researchers at Cold Spring Harbor Laboratory (CSHL), US, discovered that preventing PDAC cells storing cholesterol halted cancerous cell growth in mice and lab-grown pancreas models.
The team, led by Dr David Tuveson, professor at CSHL, set out to understand why pancreatic cancer cells produce huge volumes of cholesterol. They explained: “Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumour progression.”.
The researchers identified that the pancreatic cancer cells were making far more cholesterol than was needed to support the growth of their membranes (in which some cholesterol is an essential component). This was unusual, said Tobiloba Oni, a graduate student in Tuveson’s lab, as cells typically make only as much cholesterol as they need and, as a result, “the cholesterol pathway is one of the most regulated pathways in metabolism.”
However, the team identified that the cancer cells were converting the cholesterol they were producing into a form that can be stored in the cell. Free cholesterol never accumulates so, to produce the required levels, the synthesis pathway keeps churning out more. The scientists found SOAT1 was the enzyme responsible for converting free cholesterol to its stored form and which pancreatic cancer cells have an abundance of.
Experimenting with the genetic elimination of SOAT1 caused the cancer cells to stop proliferating and stalled tumour growth in animal models. However, the effect was only evident in cells with mutations in both copies of p53, a tumour suppressor gene. According to the team, the ‘normal’ cells without this mutation continued to function as usual without the SOAT1 enzyme, suggesting the team had identified a target that could be used to specifically target cancers.
Mutations in p53 promote cancer growth, proliferation and survival. They are very common in many cancers, including pancreatic cancers.
The team concluded that they hope this novel target will lead to the development of novel, highly specific drugs, able to treat cancers without the extensive side-effects associated with non-specific therapies.