Role of the Chromosome 19 MicroRNA Cluster in Liver Cancers

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Project Summary The chromosomal 19 microRNA cluster (C19MC) is a regulatory part of the genome normally only active during embryological development and in the placenta. Recently, Dr. Brohl has led work showing that extreme overexpression of C19MC is a genomic hallmark of a rare cancer, undifferentiated embryonic sarcoma of the liver [UESL] (Setty BA… Brohl AS, PLOS genetics, 2020). Further, he has shown that C19MC overexpression is frequent amongst most common adult cancers and that overexpression is linked to important phenotypic changes. Consistently across cancer types, for example in breast cancer (Jinesh GG…Brohl AS, PLOS One, 2018) and hepatocellular carcinoma [HCC] (Jinesh GG…Brohl, AS, Scientific Reports, 2020), C19MC is linked to an undifferentiated status, stem-like features, and therapy resistance. In this proposal, Dr. Brohl aims to further investigate the role of C19MC in liver cancers, including both HCC and UESL. In parallel study of the same molecular feature in both a rare tumor and common cancer will allow him to utilize the advantages of both: genomic and phenotypic uniformity of the rare cancer will enhance the ability to isolate the effects of the genomic feature of interest, diversity and availability of numerous model systems of the common cancer will facilitate study of replicability and evaluation of the scope of findings. Importantly, Dr. Brohl will generate new models, including CRISP/Cas9 knockdown and induction of C19MC expression that will be valuable for the scientific community not only for cancer biology but for anyone interested in the study of C19MC (e.g. placental research). Dr. Brohl is well positioned to lead this proposal. He has already established himself as a clinical expert in the care of patients with rare tumors, has a robust record of translational genomics research, and has been principally responsible for the preliminary scientific findings supporting this work. He will be primarily mentored by Dr. Elsa Flores, a well-funded senior scientist who has substantial experience and expertise in molecular oncology and non-coding RNA biology. The wet-laboratory component of this proposal will be conducted in shared space from her lab and with her direct input. The proposal includes a career development plan and research plan that will provide Dr. Brohl with the expertise and data necessary to reach his goal of becoming an independent physician-scientist. In addition to Dr. Flores, his mentorship and advisory team includes Dr. Damon Reed, a senior clinical and translational researcher with expertise in adolescent and young adult cancers, and Dr. Richard Kim, a clinical researcher and thought leader in the treatment of hepatocellular carcinoma. Upon completion of this proposal, Dr. Brohl will be well positioned to transition to research independence. He plans to submit an R01 during the penultimate year of this award based on the results generated from this work.