Fox Chase Cancer Center researchers identified anoctamin 6 (ANO6) as a therapeutic target in pancreatic ductal adenocarcinoma. In preclinical studies, blocking ANO6 in cancer-associated fibroblasts disrupted trogocytosis—a mechanism where cancer cells extract cholesterol and lipids from surrounding tissue—while reducing T-cell exhaustion and significantly slowing tumor growth in mouse models.
Identification of ANO6 as a target
- ▪Fox Chase Cancer Center researchers identified anoctamin 6 (ANO6) as a potential therapeutic target that regulates lipid transfer and immune suppression in pancreatic ductal adenocarcinoma.
- ▪Fox Chase Cancer Center researchers found that reducing anoctamin 6 (ANO6) expression disrupted a stromal synapse-mimicry circuit that coordinates tumor nutritional support, CAF-unit metabolism, and immune suppression.
- ▪Anoctamin 6 (ANO6) is a phospholipid scramblase highly expressed in cancer-associated fibroblasts within pancreatic tumor microenvironments.
Effects of ANO6 inhibition in mouse models
- ▪In mouse models of pancreatic cancer, tumors supported by cancer-associated fibroblasts with functional anoctamin 6 grew substantially faster than tumors lacking functional anoctamin 6.
- ▪Treatment with the anoctamin 6-inhibiting drugs niclosamide or clofazimine significantly reduced pancreatic tumor weight in preclinical mouse models.
- ▪In preclinical models, niclosamide treatment reduced the delivery of cholesterol from cancer-associated fibroblasts to pancreatic ductal adenocarcinoma cells.
Lipid delivery from CAFs to cancer cells
- ▪Pancreatic cancer cells deficient in Nsdhl died in lipid-poor media but survived when co-cultured directly with cancer-associated fibroblasts or supplied with low-density lipoprotein cholesterol.
- ▪Pancreatic ductal adenocarcinoma lacks functional blood vessels and consists mostly of dense connective tissue populated by cancer-associated fibroblasts, limiting direct nutrient delivery from bloodstream vessels.
- ▪Intravital microscopy experiments demonstrated that blood-borne low-density lipoprotein particles concentrate first in cancer-associated fibroblasts before migrating to pancreatic ductal adenocarcinoma cells over an 18-hour period.
Characteristics of CAF membrane trogocytosis
- ▪In laboratory experiments, depletion of anoctamin 6 or TMEM30A in cancer-associated fibroblasts suppressed the trogocytic transfer of membranes to pancreatic ductal adenocarcinoma cells.
- ▪Membrane transfer via trogocytosis between cancer-associated fibroblasts and pancreatic cancer cells is temperature-dependent and requires calcium and magnesium, while remaining unaffected by the dynamin inhibitor Dynasore.
- ▪Trogocytosis is a process where pancreatic ductal adenocarcinoma cells acquire membrane fragments, cholesterol, and lipids through direct contact with cancer-associated fibroblasts.
Immune suppression via CAF trogocytosis
- ▪Cytotoxic T lymphocytes form direct contacts with cancer-associated fibroblasts and acquire membrane material containing excess cholesterol within the pancreatic tumor microenvironment.
- ▪Cancer-associated fibroblasts suppress immune response in pancreatic ductal adenocarcinoma by transferring plasma membrane fragments to cytotoxic T lymphocytes through anoctamin 6-dependent trogocytosis.
- ▪Accumulation of excess cholesterol transferred from cancer-associated fibroblasts contributes to T-cell exhaustion, reducing the ability of cytotoxic T lymphocytes to kill pancreatic cancer cells.
- ▪Laboratory experiments showed that cytotoxic T lymphocytes exposed to cancer-associated fibroblasts with reduced anoctamin 6 displayed greater cancer-killing activity and decreased markers of T-cell exhaustion.
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