Thursday, November 21, 2024
11/21/2024
Abstract Hepatocellular carcinoma (HCC) is a deadly cancer with poor prognosis and limited therapeutic options. Biopsies are contraindicated in HCC, restricting our ability to identify unique tumor drivers and subsequent therapeutic targets. Innovative target identification for HCC treatment is thus a critical research gap. Our lab has previously established focal adhesion kinase (FAK) as a driver of HCC, with 16% of HCC patients presenting with an amplification of the PTK2 gene that encodes FAK. However, the mechanism of FAK in HCC tumor promotion remains unknown. After treatment with a proteolysis-targeting chimera for FAK in HCC cell lines, unbiased RNA-sequencing showed that connective tissue growth factor (CTGF) was significantly downregulated following the pharmacological degradation of FAK. CTGF has recently been established as a tumor promoter across several cancer types, but its role in HCC remains elusive. CTGF is secreted from cells and can be detected in conditioned media in vitro and serum in vivo. Preliminary work in HCC cell lines has confirmed a relationship between FAK expression and CTGF expression under several different conditions. CTGF expression and secretion is decreased following the degradation of FAK; CTGF expression and secretion is increased following FAK overexpression; and basal expression levels of FAK and CTGF show high correlation across a panel of HCC cell lines. Furthermore, the knockdown of CTGF was found to significantly inhibit cell growth both in vitro and in vivo. Given this preliminary data, we hypothesize that FAK promotes CTGF expression, and CTGF in turn promotes HCC. Furthermore, we hypothesize that serum CTGF levels can be used as a surrogate marker for FAK expression and/or activity in HCC, indicating the utility of a FAK-targeting treatment in the clinic. We will address these hypotheses by (1) determining the mechanism through which FAK promotes CTGF expression in HCC, (2) evaluating the contribution of CTGF to HCC growth, and (3) determining if CTGF serum levels are correlated to tumor FAK protein and FAK Y397 phosphorylation levels in HCC mouse models and patient samples. This study will utilize a combination of in vitro and in vivo models as well as patient samples obtained from clinical collaborators. Overall, this study will characterize a novel tumor-promotion pathway and elucidate a unique predictive biomarker in HCC.
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