PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a lethal solid tumor that is highly dependent on recruitment of new blood vessels and has no common genomic targets. As for most solid tumors, metastasis causes a disproportionate degree of morbidity and mortality. LIN28B – an RNA-binding protein expressed in tumors and in developing tissues – is essential for HCC development and elevated LIN28B expression in HCC correlates with an increased risk of death. We recently identified LIN28B as a novel driver of pancreatic cancer metastasis and propose in Aim 1 to use an integrated series of molecular, cellular, and animal experiments to determine if HCC metastasis is driven by LIN28B. In Aim 2, I propose to couple robust co-culture (HCC cell and endothelial cell) in vitro and in vivo models to define how LIN28B expression in HCC cells modulates its effect on endothelial cells, which in turn stimulate the HCC metastatic phenotype. In Aim 3, I will utilize our expertise in novel circulating tumor cell purification/analysis technologies and computational analysis of conventional and novel tissue staining technologies to characterize the metastasis-driving and endothelial regulatory roles of LIN28B using primary human circulating tumor cell and tumor tissue specimens. Collectively, this work will provide functional rationale for the development of new therapies targeting the LIN28B pathway and linked vascular-regulatory pathways in HCC and for the development of novel matched biomarkers. The applicant, Dr. Joseph Franses, is an oncologist at the University of Chicago Cancer Center. He will spend 75% of his time performing translational research and 25% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational research. Dr. Franses has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He has established collaborations with experts in cancer genomics, molecular biology, tumor animal modeling, and computational biology to provide experimental advice and specific training in the field. Dr. Franses will conduct this research and leverage the exceptional research and teaching environment at the University of Chicago Cancer Center. The University of Chicago harbors an outstanding research community and has a long track record for successful mentorship of independent physician-scientists. This will be an ideal environment for successful completion of these experiments and the realization of Dr. Franses’ career goal of becoming an independent physician-scientist dedicated to improving the care of patients with gastrointestinal cancers.