Mitochondrial Quality Control Adaptations Support Malignant Progression of Serous Ovarian Cancer Cells and Spheroids
| dc.contributor.author | Grieco, Joseph Patrick | en |
| dc.contributor.committeechair | Schmelz, Eva Maria | en |
| dc.contributor.committeemember | Craige, Siobhan | en |
| dc.contributor.committeemember | Pickrell, Alicia M. | en |
| dc.contributor.committeemember | Smyth, James | en |
| dc.contributor.department | Graduate School | en |
| dc.date.accessioned | 2022-04-27T08:00:14Z | en |
| dc.date.available | 2022-04-27T08:00:14Z | en |
| dc.date.issued | 2022-04-26 | en |
| dc.description.abstract | Serous ovarian cancer is the 5th leading cause of cancer-related deaths in women, with a 30% survival rate when spread into the highly hypoxic and visceral peritoneal cavity. Despite efforts to treat this highly metastatic disease, traditional chemotherapeutic and cytoreductive therapies are unable to diminish or induce cell death of circulating metastases from colonizing secondary sites due to their genetic and histologic heterogeneity and development of drug resistance. The dissemination route for primary metastasis, however, is most often conserved to the peritoneal cavity, which is low in nutrients and hypoxic (1-2% O2). Cells exfoliated from the primary tumor will aggregate during migration, which elicits a survival signal to maintain viability in this environment. The underlying cellular and molecular changes involved with aggregation have yet to be determined. We have previously found that aggregation of murine ovarian surface epithelial (MOSE) cells present a more suppressed metabolic phenotype upon aggregation. My research sought to identify how the mitochondria were internally regulated to support malignant transformation, migration, and invasion through modulation of quality control, mitochondrial dynamics, mitophagy, and mitobiogenesis. We have shown that aggregation of cancer cells supports increased mitochondrial fragmentation localized to the hypoxic core of our spheroid models. Further, aggregation supports enhanced viability through an upregulation of cancer genetic pathways associated with cell death, proliferation, stemness, and epithelial mesenchymal transition (EMT). Nutrient deprivation during migration further enhanced mitochondrial fragmentation and induction of mitophagy to prevent activation of apoptosis. Additionally, we have identified a phenotypic switch from enhanced mitophagy during peritoneal dissemination that supports survival of ovarian cancer cell aggregates to mitochondrial biogenesis during secondary tissue colonization that enables proliferation upon invasion. We have associated these changes with an increased bioenergetic proliferative niche through inhibition of proliferation, migration, and mitochondrial translation. This research has contributed to the understanding for the role of mitophagy as a survival rather than apoptotic signal in cancer cells as adaptation to nutrient-deprived environments, while also identifying how these processes can be reversed upon adhesion to support invasion and metastatic capacity during secondary colonization. This research is significant because it will identify molecular adaptations associated with the viability of disseminating cancer metastases as well as promote novel preventative therapeutics that can be used to limit the mortality of highly aggressive ovarian cancer in women. | en |
| dc.description.abstractgeneral | Ovarian cancer continues to be one of the highest contributors of gynecologic cancer-related deaths in women. This is due to limited symptomology, biomarker availability, and screenings for patients. Women are mostly diagnosed when the disease has already spread throughout the abdominal cavity which makes treatment much more difficult and, accordingly, the survival rate is much lower. Ovarian metastases mostly spread throughout the peritoneal cavity. Interestingly, this cavity has been identified to being limited in nutrients and oxygen that are essential for survival thus suggesting that these cancer cells must adapt to these harsh conditions to remain viable. We have previously observed that the cancer cells are able to clump together, and form 3D structures known as spheroids which have drastically reduced their proliferation and appear highly resistant tor treatment than single cells. In this project, we wanted to determine how the mitochondria (primary energy producers) were structurally changing in response to the formation of these spheroids and in nutrient- and oxygen-starved conditions. We have found that these organelles become much smaller and circular in low-oxygen conditions, especially in the center of the spheroids. Further, we found changes in cancer- and mitochondrial-related pathways during spheroid formation which could further support survival. Finally, we found that key functions related to the mitochondrial quality control and enhanced mitochondrial content and activity are switched when changing nutrient availability from low oxygen and nutrient conditions to oxygenated and nutrient-rich conditions and generate conditions that allow the spheroids to attach to abdominal organs and form secondary tumors. This research is important because it suggests new possible markers that can be used as therapeutic targets to prevent these aggressive functions associated with more terminally staged disease. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:34330 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/109754 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | Creative Commons Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
| dc.subject | mitochondria | en |
| dc.subject | ovarian cancer | en |
| dc.subject | mitophagy | en |
| dc.subject | mitochondrial dynamics | en |
| dc.subject | mitobiogenesis | en |
| dc.subject | viability | en |
| dc.subject | reactive oxygen species | en |
| dc.subject | spheroid | en |
| dc.title | Mitochondrial Quality Control Adaptations Support Malignant Progression of Serous Ovarian Cancer Cells and Spheroids | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Translational Biology, Medicine and Health | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |