Researchers led by Fox Chase Cancer Center have identified anoctamin 6, or ANO6, as a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer. Their findings indicate that the protein helps tumor cells obtain cholesterol and other lipids from surrounding cells while contributing to immune suppression.
The study focused on cancer-associated fibroblasts (CAFs), which form much of the dense connective tissue surrounding pancreatic tumors. Because this tissue has relatively few functional blood vessels, how cancer cells obtain essential membrane lipids has remained unclear. The researchers found that CAFs can acquire cholesterol from the bloodstream and pass it to nearby cancer cells through trogocytosis, a contact-dependent process in which cells take fragments of another cell’s membrane.
ANO6 helps prepare CAF membranes for this transfer. When researchers reduced or eliminated the protein in CAFs, those cells were less able to support pancreatic cancer cell survival. In mouse models, tumors associated with CAFs containing functional ANO6 grew faster than tumors supported by CAFs lacking the protein.
The same mechanism also affected the immune response. CAFs can interact directly with cytotoxic T lymphocytes, immune cells capable of recognizing and killing cancer cells. During these contacts, T cells acquire CAF membrane material, including cholesterol. The researchers linked this excess cholesterol to T-cell exhaustion, which can weaken the cells’ anticancer activity.
In mouse experiments, ANO6 blockade reduced cholesterol accumulation in tumor-infiltrating T cells and improved indicators of T-cell function. Laboratory tests also found that T cells exposed to CAFs with reduced ANO6 showed greater cancer-killing activity.
The researchers additionally tested niclosamide and clofazimine, drugs that inhibited ANO6-dependent activity in the study. Treatment with either compound significantly reduced tumor weight in mouse models, while niclosamide also decreased cholesterol delivery to pancreatic cancer cells.
The findings were published in Nature Cancer in a paper describing ANO6-mediated trogocytosis by CAFs as a process that promotes pancreatic cancer growth and immune suppression. The researchers cautioned that trogocytosis is only one of several possible routes by which pancreatic cancer cells obtain lipids, and that the tested drugs may affect targets beyond ANO6. Further work is therefore needed to determine whether selective ANO6 inhibitors could become an effective treatment for PDAC or other cancers with dense, CAF-rich tumor tissue.