Resolving and Targeting the Mechanobiome of Pancreatic Ductal Adenocarcinoma

Abstract

In the US, 37,000 people die annually from pancreatic ductal adenocarcinoma (PDAC), which has an abysmal 6% five-year survival rate. Existing strategies for treating cancer primarily focus on inhibiting cell growth through specific genetic pathways, which typically either fail to completely abolish the disease or which lead to compensatory regulatory changes, and hence, drug resistance. Targeting cell mechanics remains an under-used approach for drug development.To identify new targetable drug spaces we assessed cytoskeletal proteins in the PDAC mechanobiome, the direct driver of cell shape change including migration and invasion. The structural elements of the mechanobiome are the final determinants of a cell's mechanical attributes and lie downstream of regulatory molecules like KRAS. Inhibition of these targets is therefore less likely to be subject to compensatory regulation by cancer cells. We determined via western blot analysis and immunohistochemistry of patient-derived samples that key players involved in mechanosensation-myosin IIA, IIC, α-actin-4, and filamin B -show increased expression in cancerous ductal epithelial over normal tissue, while non-mechanosensory, or variable mechanosensory, paralogs (myosin IIB, α-actin-1, and filamin A) show decreased expression. This upregulation of highly mechanosensory proteins has initiated an investigation into the necessity and sufficiency of the myosin II paralogs in PDAC metastasis through overexpression and knockdown of expression, coupled with mechanical assays. In addition to resolving the mechanobiome of PDAC, we have previously shown that targeting of myosin IIC by 4-hydroxyacetophenone affects PDAC mechanics. We are testing the in vivo efficacy of 4-HAP by conducting a murine multi-arm study of metastatically human derived pancreatic cancer cells. Preliminary results suggest a protective effect against the metastasis of human pancreatic cancer cells among mice treated with 4-HAP every other day.