Epithelial-Mesenchymal Status Predics Tumor Agressivenss, Chemoresistance and Invasiveness in High Grade Serous Ovarian Cancer
Date of Award
Master of Science in Biology
First Reader/Committee Chair
High Grade Serous Ovarian Cancer (HGSOC) is one of the deadliest gynecological diseases in the United States ranking fifth in cancer deaths among women. Approximately 22 thousand new cases are expected to occur in the year 2020, and unfortunately, it is estimated that 14 thousand women will succumb to the disease; the incidence to death ratio, 64%, remains high despite current research. Current treatment includes debulking surgery followed by combinatorial chemotherapeutics with platinum-based and taxol-based compounds. But despite aggressive surgery and standard-of-care chemotherapeutics, 80% of patients will experience a recurrence and only 15-30% of those with recurring disease will respond to further treatment.
Tumors consist of a heterogeneous population of cell types. A small minority of tumor cells, called cancer stem cells (CSCs), can self-renew and differentiate and are thought to be responsible for recurrent, chemoresistant disease. A cancer cell’s ability to migrate and invade other tissues is a hallmark of metastatic disease.
To invade, cells must undergo a process called an epithelial-mesenchymal transition (EMT) in which epithelial genes such as CDH1, which codes for E-Cadherin (E-CAD), a cell-cell adhesion molecule, are repressed by the transcription factor SNAI1 (Snail) and genes associated with a mesenchymal phenotype, such as CDH2, which codes for N-Cadherin (N-CAD) are upregulated. This switch from epithelial to mesenchymal gene expression leads to migratory and invasive properties in cells. Cancer cells that express both epithelial and mesenchymal markers are considered hybrid (E/M) cells and are associated with increased tumor-forming ability and exhibit more cancer stem-cell (CSC) like characteristics.
Of those diagnosed with HGSOC, 50% exhibit a defect in their ability to repair DNA via homologous recombination (HR). In 20% of cases HR deficiency is caused by a mutation in the breast cancer susceptibility (BRCA) 1 or 2 gene which code for proteins that participate in the HR pathway. HR deficient cancer cells rely heavily on the poly (ADP-Ribose) polymerase (PARP) family of proteins to repair DNA damage. For this reason, PARP inhibitors have recently been employed as an adjuvant to chemotherapy to induce synthetic lethality, but some cancers develop a resistance which renders the therapy ineffective. In addition, some studies suggest that the use of PARP inhibitors, such as olaparib, enrich for cell surface markers CD133+ & CD117+. These markers are indicative of the cancer stem cell phenotype in HGSOC. Although use of PARP inhibitors has increased progression-free survival, more information regarding the PARP protein and its functions is needed.
In this study, we characterized six patient derived samples according to their functional capabilities related to invasiveness, chemoresistance and CSC properties and evaluated these capabilities in parallel with their EMT status. We found that certain EMT sub-types exhibit different capabilities and the most hybrid sub-type, E/M hybrid, are the most aggressive in tumor formation. This data suggests that determining EMT status could be valuable in predicting patient outcomes and developing personalized therapies.
Sanderman, Linda, "Epithelial-Mesenchymal Status Predics Tumor Agressivenss, Chemoresistance and Invasiveness in High Grade Serous Ovarian Cancer" (2020). Electronic Theses, Projects, and Dissertations. 1096.
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