Identification of Novel Ovarian Cancer Oncogenes that Function by Regulating Exosome Function
Abstract
Epithelial ovarian cancer affects approximately 21,000 women a year in the United States, resulting in 14,000 deaths. Standard treatment includes debulking surgery followed by platinum chemotherapy. Even though for most women this treatment reduces tumor burden to undetectable levels, the vast majority of these women (>75%-80%) will develop recurrent tumors resistant to conventional therapeutics. Patients will die of progressively chemotherapy-resistant tumors. There is a major need to identify biological drivers of these cancers that can be used as targets for the establishment of novel treatments. We have identified Synaptotagmin-like 2 (SYTL2) as a potential driver gene of epithelial ovarian cancers. SYTL2 was found to be amplified in 25% of ovarian cancer patients and is associated with significantly poorer overall survival. Even though SYTL2 remains a largely uncharacterized protein, previously published data indicate its involvement in vesicle secretion through interaction with proteins belonging to a family of functionally similar enzymes called GTPases. Exosomes are 30-100 nm membrane-bound vesicles secreted by various types of cells during normal physiological as well as pathological processes. Solid tumors release large quantities of exosomes transporting nucleic acids and proteins to support tumor growth, dissemination and metastasis, resistance to therapy, and suppression of the host immune system. We have identified at least 14 genes that regulate exosome secretion and correlate with poor prognosis of ovarian cancer patients. The list includes SYTL2 and 4 members of the GTPase family, Rab2b Rab 27 a and b, and Rab31. These are described to regulate exosome secretion, be members of the Ras oncogenic pathway, and induce cellular oncogenic behavior. We hypothesize that SYTL2 and the Rab superfamily of GTPases represent a new class of oncogenes that promote tumor progression by regulating exosome secretion and modulating communication between cancer cells and their environment. Our data indicate that overexpression of SYTL2 in an ovarian cancer cell line increases exosome secretion and induces cells proliferation, migration, and cisplatin resistance, thus highlighting the tumorigenic role of this gene and its association with exosome release. The goal of this project is to investigate whether SYTL2 and members of the Rab superfamily regulate the release of exosomes and analyze how this modulates the biology of ovarian cancer cells and its clinical features. The identification of genes that regulate the communication mechanisms between cancer and host cells represents a unique opportunity to establish novel therapies that interrupt this process. This approach will improve management of these tumors by decreasing tumor dissemination, angiogenesis, immune suppression and chemoresistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610593
Entities
People
- Michael Birrer
Organizations
- Massachusetts General Hospital
- United States Army