Project 3 is designed to determine the roles of class I and II histone deacetylase (HDAC I/II), glycogen synthase kinase-3? (GSK-3?), Yes-associated protein (YAP) and downstream signaling pathways involving the macrophage-stimulating protein (MSP) and its receptor, RON (Recepteur d'Origine Nantais) kinase, in promoting cancer metastasis in the liver. The project considers these cancer cell pathways and the recruitment of hepatic stellate cells (HSCs) and Kupffer cells (macrophages in the liver) to constitute a microenvironment for enhancing the growth of the metastasis. The potential role of these pathways on cancer metastasis comes from our observations in metastasis promotion using a new chemical entity we designed to inhibit HDAC I/II and GSK-3?, two key enzymes that are overactivated in pancreatic, prostate and colorectal cancer. Further, our preliminary shows roles for HDAC I/II and GSK-3? in regulating YAP, MSP, RON and metastasis. Based on preliminary results, we propose the following specific aims: (1) to investigate the mechanisms by which HDAC and GSK-3? regulate YAP signaling in cancer cells to promote the growth of metastasis in the liver; and (2) to investigate the regulation and role of YAP signaling in HSCs for remodeling of cancer microenvironment in the liver to promote the growth of liver metastasis. In collaboration with other projects of this Program, Project 3 will study the roles of YAP and MSP/RON signaling in pancreatic, colon, and prostate cancers and determine the relationship of these signals with fatty liver and high fat diet. The outcomes of this project will significantly enhance our understanding of the mechanisms underlying the promotion of cancer metastasis to the liver, with clear insights for application of the knowledge to the prevention and treatment of cancer metastasis.
We have designed a chemical entity that inhibits two key enzymes overactivated in pancreatic, colorectal, and prostate cancer cells, histone deacetylase (HDAC) and glycogen synthase kinase- 3? (GSK-3?), and preliminary results show that it has significant effects on cancer cell metastasis to the liver in animal models of pancreatic cancer. Based on these results and our knowledge of the interactions of cancer cells in the microenvironment of the primary cancer, we hypothesize that the two enzymes play a critical role in developing a microenvironment in the liver to promote cancer metastasis progression. The results of this project, in collaboration with others in the Program, will provide essential information to develop therapeutics for the prevention and treatment of metastases to the liver, a serious unmet medical need.