Mouse studies tie ANO6 to lipid transfer and weakened T cells in pancreatic tumors, pointing to a potential target that could affect both processes.
ANO6 appears to help pancreatic tumors solve two problems at once: getting nutrients in a tissue with poor blood supply and limiting the activity of cancer-killing T cells. In preclinical studies led by Fox Chase Cancer Center researchers, blocking the protein slowed tumor growth and reduced signs of immune suppression in mice.
The findings point to anoctamin 6 (ANO6) as a possible therapeutic target in pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer. The study, published in Nature Cancer, describes how ANO6 supports the transfer of lipids from cancer-associated fibroblasts (CAFs) to nearby cancer cells. It also links the same transfer process to changes that can exhaust cytotoxic T lymphocytes, or CTLs.
Igor Astsaturov, MD, PhD, a Fox Chase professor and co-senior author, said the results help explain how cancer cells secure nutrients within the distinctive structure of pancreatic tumors. “Cancer-associated fibroblasts are not passive bystanders. They actively support tumor growth by transferring lipids to cancer cells.”
Fibroblasts supply lipids through cell contact
PDAC tumors are wrapped in dense connective tissue. CAFs and the collagen fibers they produce contribute to this tissue, while expanding tumor structures can collapse blood vessels. That combination leaves cancer cells with limited access to nutrients from the circulation. How they obtain cholesterol and other membrane-building lipids in this setting has been an open question.
The researchers found that CAFs can take up cholesterol from the bloodstream and pass it to pancreatic cancer cells through trogocytosis. In this contact-dependent process, one cell takes small fragments of another cell’s plasma membrane. The cancer cells “nibble” pieces from CAF membranes, gaining cholesterol and other lipids that support survival and growth.
Edna Cukierman, PhD, a Fox Chase professor and co-leader of its Cancer Signaling and Microenvironment Program, said the team observed the transfer in laboratory and animal models. The process depends on ANO6, which helps prepare the CAF membrane for transfer. When researchers lowered or eliminated ANO6 in CAFs, those cells became less effective at supporting cancer cell survival. Tumors supported by CAFs with functional ANO6 grew faster in mouse models than those without it.
The researchers described their findings in the paper “ANO6-mediated trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer cell growth and immune suppression”. They report that blocking ANO6 countered tumor growth in part by disrupting cholesterol delivery, while also easing immune suppression.
The same transfer may weaken T cells
CAF contact has implications beyond tumor nutrition. The study found that CAFs also interact directly with CTLs, immune cells capable of recognizing and killing cancer cells. During these encounters, T cells can take up CAF membrane material, including cholesterol. The researchers link this transfer to T-cell exhaustion, a state in which the cells become less effective.
In mouse studies, blocking ANO6 reduced cholesterol accumulation in T cells inside tumors and improved markers of T-cell activity. Laboratory experiments likewise showed greater cancer-killing activity in T cells exposed to CAFs with reduced ANO6.
“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. He conducted the work with Serge Fuchs, a professor at the University of Pennsylvania and a co-author. In their view, interfering with ANO6 could disrupt both functions.
Cukierman said lowering ANO6 also disrupted a “stromal synapse-mimicry circuit” the team had previously identified, which coordinates nutritional support for tumors, CAF metabolism and immune suppression. The researchers see ANO6 as a link between these processes.
Drug results are promising but preliminary
The team tested niclosamide and clofazimine, drugs that inhibited ANO6-dependent activity in the study. Both reduced tumor weight in mouse models, and niclosamide also lowered cholesterol delivery to pancreatic cancer cells.
Those results don’t establish that either drug’s antitumor effect comes solely from ANO6 inhibition. The researchers acknowledge that both compounds may act on other targets, and that pancreatic cancer cells may obtain lipids through additional routes. They say further work is needed to test whether selectively targeting ANO6 can provide an effective treatment strategy.
For now, the mouse findings offer a way to investigate how nutrient transfer and immune suppression intersect in CAF-rich pancreatic tumors. The researchers describe niclosamide and clofazimine as starting points for testing the approach, while calling for selective ANO6 inhibitors to clarify the protein’s role. If that role holds up in further studies, targeting ANO6 could affect both the tumor’s lipid supply and the pressure CAFs place on cancer-fighting T cells.
The post Blocking Protein Slows Pancreatic Tumor Growth and Reduces Immune Suppression in Mice appeared first on GEN - Genetic Engineering and Biotechnology News.
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