Pancreatic cancer is driven by risk factors such as diabetes and chronic pancreatic injury, which are further associated with gut
dysbiosis. Intestinal toxins such as
bile acids and bacterial
endotoxin (LPS), in excess and persistence, can provoke chronic
inflammation and
tumorigenesis. Of interest is that many intestinal toxins are negatively charged acidic components in essence, which prompted us to test whether
oral administration of cationic resin can deplete intestinal toxins and ameliorate
pancreatic cancer. Here, we found that increased plasma levels of
endotoxin and
bile acids in Pdx1-Cre: LSL-KrasG12D/+ mice were associated with the transformation of the
pancreatic ductal carcinoma (PDAC) state. Common bile-duct-
ligation or LPS injection impeded autolysosomal flux, leading to Yap accumulation and malignant transformation. Conversely,
oral administration of
cholestyramine to sequestrate intestinal
endotoxin and
bile acids resumed autolysosomal flux for Yap degradation and attenuated metastatic incidence. Conversely,
chloroquine treatment impaired autolysosomal flux and exacerbated malignance, showing jeopardization of p62/ Sqxtm1 turnover, leading to Yap accumulation, which is also consistent with overexpression of
cystatin A (CSTA) in situ with
pancreatic cancer cells and metastatic
tumor. At cellular levels,
chenodeoxycholic acid or LPS treatment activated the
ligand-receptor-mediated AKT-mTOR pathway, resulting in autophagy-lysosomal stress for YAP accumulation and cellular dissemination. Thus, this work indicates a potential new strategy for intervention of pancreatic
metastasis through sequestration of intestinal acidic toxins by
oral administration of cationic resins.