Monday, June 9, 2025
6/9/2025
Examining the role of the miR-181a:Wnt/B-catenin axis in ovarian cancer - Project Summary/Abstract High grade serous carcinoma (HGSC) the most common type of “ovarian” cancer is one of the deadliest cancers diagnosed in women. One of the primary drivers for the high mortality rate associated with HGSC is tumor recurrence and chemoresistance. Thus, there is a critical need to identify the genetic drivers of tumor development and recurrence to improve therapeutic strategies. In this proposal, we provide extensive evidence for the clinical and biological importance of miR181a, which is amplified in a large majority of HGSC patients, correlates with poor overall survival, and induces epithelial to mesenchymal transition (EMT), metastasis, drug resistance, and stem-like cell properties. Remarkably, this correlation between miR181a with clinical outcome and recurrence has also been shown in numerous other cancers. Notably, miR181a expression in HGSC tumors offered stronger prognostic value than established clinical biomarkers. Furthermore, analysis of >10,000 tumors representing 20 different cancers revealed that amplification of miR181a correlated with poor outcome. Most recently, we have uncovered a novel mechanism through which miR181a can drive tumor development at the earliest stage through the cooperative targeting of RB1 and Stimulator of Interferon Genes (STING). Enhanced miR181a promoted the growth of highly aggressive and genomically instable cells through the direct inhibition of STING, a key activator of interferon signaling in response to cytoplasmic DNA. Though activating anti-tumor immunity is increasingly being recognized as an important therapy in cancer treatment the efficacy of current immunotherapies for the treatment of HGSC has not been successful mainly due to the highly immunosuppressive microenvironment. One of the primary means by which a tumor creates an immunosuppressive microenvironment is by inhibiting STING signaling within the tumor. Thus, our novel finding showing that miR-181a directly regulates STING introduced unique opportunity to assess whether therapeutic targeting of the miR-181a will reactivate IFN signaling via STING to overcome immune tolerance that is commonly seen in HGSC tumors. We will interrogate the cooperativity between miR181a and STING through the following aims: 1) Determine the effect of miR181a loss on immune cell infiltration and IFN signaling using patient-derived organoids in the presence and absence of either a STING agonist or anti-PDL1, 2) Ascertain the role of miR181a on the sensitivity to STING agonist or anti-PDL1 in vivo, 3) Assess whether miR181a activation is sufficient to drive tumor formation alone or in combination various combinations of tumor suppressor genes in mice. Through these complementary studies, the goal is to characterize the mechanism by which miR181a regulation of STING can re-engage the cytotoxic anti-viral signaling machinery in HGSC and assess how miR181a is promoting tumor development.
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