Hedgehog and YAP signaling in fibrolamellar carcinoma: Tumor-stroma crosstalk and thecancer stem cell niche 2017 – 2019
Principal Investigators: Cynthia Guy, MD, Associate Professor of Pathology; Anna Mae Diehl, MD, Florence McAlister Professor of Medicine, Duke University School of Medicine
Fibrolamellar carcinoma has a unique appearance; it is made up of large tumor cells surrounded by thick fibrous bands (the stroma). We believe that the cancers growth may result from deregulated communications signals between the tumor cells and cells that produce the stroma.
The major producers of stroma in the liver are called hepatic stellate cells (HSCs). Evidence from our laboratory has shown that in many different types of liver disease, HSCs promote repair of damaged livers by producing stroma and sending out signals that help surviving liver cells to regenerate. When repair is effective, stroma transiently accumulates and then regresses as healthy liver tissue is regenerated. However, when repair becomes dysregulated, excessive stroma (a.k.a., scar) accumulates and regeneration stalls before recovery of healthy liver tissue is accomplished. Our research revealed that HSCs regulate repair by controlling the activity of the Hedgehog (Hh) signaling pathway. We have demonstrated that while Hh signaling is helpful during normal liver development and repair, if it becomes deregulated, it can result in lead to pathologic processes. These processes include fibrosis (scarring) and the activation of a downstream signaling pathway that leads to the activation of Yap, a factor that can make liver cells become more primitive (and in many ways like cancer stem cells). Thus, dysregulation of Hh and Yap results in accumulation of stroma (scar) and primitive stem-like cells and as such, resembles key features of fibrolamellar carcinoma (FLC).
Given this background, we will evaluate evidence for and against the concept that Hh and Yap signaling between the tumor cells and the stroma is important for FLC growth, and for the perpetuation of cancer stem cells. This possibility is supported by a recent publication by a FCF- sponsored investigator, Lola Reid, PhD, who showed that malignant fibrolamellar cells produce Hh protein. Furthermore, there is growing evidence that Hh and Yap interact to control liver growth. However, to date, neither pathway has been formally studied in FLC, or considered as a possible diagnostic or therapeutic target in this cancer. Our project is the first to explore this possibility and offers the promise of novel interventions to prevent and treat this devastating disease. We will examine human fibrolamellar carcinoma samples to look for evidence of Hh and Yap signaling in the tumor cells and stroma. In addition, we will grow cells in culture with and without different types of HSCs to find the best cell-cell signals to target for anti-cancer therapy.