Dr. Means research investigates the mechanisms by which tumor cells communicate with surrounding cells to regulate cancer progression. Much of this work focuses on signaling downstream of the growth factor TGF Beta. Canonical TGF Beta signaling is completely dependent on the SMAD4 protein which is a tumor suppressor in a number of solid tumors, with loss of SMAD4 decreasing progression-free survival and/or overall survival. Our studies focus on how TGF Beta/SMAD4 regulate tumor progression in colon cancer, pancreatic cancer, and oral cavity squamous cell carcinoma. We have found that epithelial SMAD4 loss has very different functions in different cancer types. In the colon, epithelial SMAD4 is a critical regulator of the inflammatory response and its loss alters the microenvironment to be pro-tumorigenic. In squamous cell carcinoma, loss of epithelial SMAD4 induces autocrine WNT signaling, making tumors less dependent upon the tumor microenvironment. In the pancreas, loss of SMAD4 determines the type of precursor that leads to cancer. We are investigating these different mechanisms both to understand the drivers of cancer progression and to identify downstream components that could be targeted clinically in SMAD4-negative tumors to improve outcomes for these patients.