Role of Mitochondrial Dynamics in Tumor Cell Plasticity and Chemoresistance During Ovarian Cancer Progression
Abstract
Ovarian cancer remains the most-deadly gynecological malignancy facing women. Although initially responsive to standard-of-care therapeutics such as Taxol and Cisplatin, ovarian cancer inevitably becomes chemoresistant and is marked by high rates of recurrence. A major trait of cancer cells is their ability to rapidly adapt to changing tumor environments during tumor progression and metastasis, which includes their ability to survive under conditions of nutrient starvation. This flexibility of tumor cells is termed tumor plasticity and also allows certain tumor clones to resist chemotherapy, resulting in inevitable recurrence of the tumor. There is a great need to identify what drives these tumor plasticity traits. Understanding these mechanisms will allow us to develop new therapeutic approaches to target tumor recurrence and chemoresistance. The overarching objective of our work is to address this gap in knowledge and our rationale is based on our novel findings that ovarian cancer cells are able to manipulate the form and function of the mitochondria as a pro-survival mechanism. Mitochondria are the powerhouse of the cell, providing the energy needed for tumor cells to grow, metastasize, and survive under different nutrient conditions. Mitochondria are also involved in regulating cell death in response to chemotherapeutic drugs. We have identified a new mechanism by which ovarian cancer cells manipulate mitochondrial function and hypothesize that this contributes to ovarian cancer cell plasticity, tumor recurrence and chemoresistance. Our TEAL expansion application focuses on a new direction based on parallel discoveries made during the pilot award period and is based on preliminary findings from extensive bioinformatics analysis of a large cohort of high-grade serous ovarian cancer specimens from the cancer genome atlas (TCGA). We discovered that ovarian cancers express a particular variant of a mitochondrial protein important in regulating mitochondrial shape and function, termed Drp1. Importantly, we found that high levels of this ovarian cancer specific Drp1 variant are associated with worse patient 5-year survival rates. We have thus discovered a new protein variant of Drp1 that affects the progression of ovarian cancer disease and leads to deleterious outcomes of high-grade serous ovarian cancer patients. Yet the specific functions of this Drp1 variant in ovarian cancer are completely unknown. In this proposal, we will address this gap in knowledge. Our preliminary data hint at why this protein is required by tumor cells and leads to worse patient outcome. We found that the ovarian cancer-specific Drp1 variant provides an important survival advantage to ovarian cancer cells by improving their mitochondrial function and allowing survival under nutrient deprivation. Moreover, we find that Drp1 not only provides cells with metabolic advantages, but also prevents cell death in response to chemotherapeutics, specifically Taxol, a drug commonly used in first line therapy. Our findings suggest that we have found a novel protein involved in cellular adaptations that allow ovarian cancer cells to survive metabolic stress and first-line chemotherapy, ultimately contributing to tumor recurrence. The specific impacts of our two study aims are listed below. Impact of Aim 1: We made a novel discovery that ovarian tumors have specific gene expression signatures of the mitochondrial fission protein Drp1. We found that specific splice variants of Drp1 are associated with different pro-tumorigenic mechanisms and that expression of one particular Drp1 variant is associated with poor patient survival. This aim is designed to make discoveries about the function of the ovarian cancer specific Drp1 protein, which is currently completely unknown in cancer. We will test the hypothesis that expression of different Drp1 splice variants contributes to tumor plasticity by manipulating mitochondrial form and fu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210252
Entities
People
- Nadine Hempel
Organizations
- United States Army
- University of Pittsburgh