Multiplatform analyses identify HCK as a novel oncogenic driver of poor-prognostic high-grade serous ovarian cancer
Creators: name: Khella, Christen
Publisher: name: No Publisher Supplied
Year: 2022

description: High-grade serous ovarian cancer (HGSOC) is the most predominant and lethal subtype of ovarian cancer. While most patients initially respond to standard-of-care treatment, the majority will eventually relapse and succumb to the disease. HGSOC patients exhibit a widely variable clinical response to standard-of-care treatments. The poor prognosis of HGSOC is commonly attributed to the late stage at which patients present with the disease, suboptimal debulking surgery, and the biological characteristics of the tumor, which lead to inherent and acquired resistance to standardized treatment options. Despite improvement in cytoreduction surgeries, treatment with combinatorial chemotherapeutic agents, and the introduction of PARP inhibitors, long-term survival rates for HGSOC have not improved over the past few decades. The mechanisms that govern the distinctions between HGSOC with good and poor prognosis are not fully understood. Therefore, understanding molecular mechanisms that result in a poor prognosis in high-grade serous ovarian cancer patients is essential for developing targeted therapies and rational personalized treatment strategies. This study sought to identify the mechanisms that drive aggressiveness and poor prognosis in HGSOC. To do so, we implemented a proteogenomic approach to analyze gene expression, proteomic and phosphoproteomic profiles of HGSOC tumor samples. Our analyses identify significant upregulation in the hematopoietic cell kinase (HCK) signaling activity in poor prognostic HGSOC patient samples. Analyses of independent gene expression datasets and immunohistochemistry of patient samples confirmed increased HCK signaling in tumors relative to normal samples and demonstrated aberrant expression in tumor epithelial cells. Consistent with the association between HCK expression and tumor aggressiveness in patient samples, in vitro phenotypic studies showed HCK promotes cell proliferation, colony formation, and invasive capacity in a panel of HGSOC cell lines. Consistently, our RPPA analysis identified downregulation of multiple cell cycle regulation and EMT markers following the inhibition of HCK. Mechanistically, we determined that HCK mediates these phenotypes through a CD44 and NOTCH3 dependent signaling axis and that inhibiting CD44 or NOTCH3, either genetically or through gamma-secretase inhibitors, can reverse back the HCK-driven phenotypes. Interestingly, our multi-platform analyses suggest that HCK may play a dichotomous tumorigenic role, as HCK was strongly associated with pro-survival signaling pathways and immunosuppressive signaling markers, including enrichment in T cell exhaustion markers and pro-tumor M2 macrophages in HGSOC patient samples. However, further analyses are needed to validate the role of HCK in regulating the immune suppressive nature of the tumor microenvironment in HGSOC. Collectively, our findings suggest that HCK may be a potential therapeutic target in a subset of aggressive and recurrent HGSOC patients.