Fox Chase Team Identifies ANO6 as Druggable Link in Pancreatic Cancer

Blocking a single membrane protein, anoctamin 6 (ANO6), significantly reduced pancreatic tumor weight in mouse models and simultaneously weakened two tumor-supporting mechanisms: lipid delivery to cancer cells and exhaustion of cancer-killing T cells. The results, from a team led by Fox Chase Cancer Center and published in Nature Cancer, identify ANO6 as a candidate therapeutic target in pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer.

The study addresses a long-standing puzzle in PDAC biology. These tumors sit inside dense connective tissue with few functional blood vessels, which collapse as cancer-associated fibroblasts (CAFs) expand and generate collagenous fibers. How cancer cells obtain membrane lipids such as cholesterol in that hostile environment remained unclear. "How PDAC cells obtain membranous lipids such as cholesterol has, therefore, remained unclear and resolving this could reveal a therapeutic strategy," the authors wrote.

What did the researchers measure?

The team found that CAFs acquire cholesterol from the bloodstream and hand it to nearby cancer cells through trogocytosis — literally "to nibble." Cancer cells pinch off small pieces of CAF plasma membrane, harvesting cholesterol and other lipids needed for survival and growth. ANO6 prepares the CAF membrane for this transfer.

The experiments separated mechanism from effect. When researchers reduced or eliminated ANO6 in CAFs, those cells lost much of their ability to support cancer cell survival. In mouse models, tumors supported by ANO6-positive CAFs grew substantially faster than tumors lacking functional ANO6. "Cancer-associated fibroblasts are not passive bystanders. They actively support tumor growth by transferring lipids to cancer cells," said Igor Astsaturov, MD, PhD, a professor at Fox Chase and co-senior author.

How does ANO6 suppress immunity?

The same mechanism works against the immune system. CAFs form direct contacts with cytotoxic T lymphocytes (CTLs), which then acquire CAF membrane material, including cholesterol. Excess cholesterol in the tumor environment contributes to T-cell exhaustion. "CAFs also inhibit T cell activity in pancreatic tumors, a major barrier to immunotherapy in this cancer type," the investigators noted.

Blocking ANO6 reversed markers of that suppression in mice. Treatment reduced cholesterol accumulation in tumor-infiltrating T cells and improved markers of T-cell activity. In laboratory experiments, T cells exposed to ANO6-reduced CAFs showed greater cancer-killing activity.

Astsaturov worked on the project with Serge Fuchs, professor at the University of Pennsylvania and co-author on the paper. "We were surprised to find that the same cellular mechanism can benefit the tumor in two ways — by supplying cancer cells with lipids while also weakening cancer-fighting T cells," Astsaturov said. "Targeting ANO6 could potentially disrupt both of these tumor-supporting functions at the same time."

Co-senior author Edna Cukierman, PhD, professor and co-leader of the Cancer Signaling and Microenvironment Program at Fox Chase, framed the finding as the capstone of her group's work: "Excitingly, reducing ANO6 expression also disrupted the stromal synapse-mimicry circuit we previously identified, which coordinates tumor nutritional support, CAF-unit metabolism, and immune suppression. These findings position ANO6 as the missing mechanistic link that unifies nearly a decade of discoveries by our team."

Which drugs did the team use?

The pharmacological evidence comes from two repurposed compounds: niclosamide and clofazimine. Both inhibited ANO6-dependent activity in the study, and both significantly reduced tumor weight in mouse models. Niclosamide additionally reduced cholesterol delivery to pancreatic cancer cells.

The authors flag the limitation themselves. "Both agents may inhibit targets unrelated to ANO6 and there remains a possibility that their antitumor activity is not exerted solely through trogocytosis," they wrote. With that caveat, they argue the compounds — described as well-tolerated and inexpensive — provide a tractable pharmacological entry point for testing ANO6 blockade and support development of selective ANO6 inhibitors for CAF-rich desmoplastic tumors.

Trogocytosis is also one of several routes by which pancreatic cancer cells may obtain lipids, and the researchers state that further work is needed to determine whether selectively targeting ANO6 is an effective treatment strategy. They suggest the same ANO6-targeting drugs may extend to other recalcitrant cancers beyond pancreatic adenocarcinoma.

Astsaturov's summary keeps the claims measured: the findings identify ANO6 as a potential target that could simultaneously disrupt the nutrient supply supporting pancreatic cancer cells and reduce the immune-suppressive effects of the tumor microenvironment. Human validation, and selective inhibitors, remain the next hurdles before this mechanism moves toward the clinic.