Abstract MIP-059: MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER
Bibliographic record
Abstract
Abstract Altered mitochondrial function remains a key feature of many tumor cells and drives pathways such gene expression, metabolic and stress responses, cell cycle progression and resistance to apoptosis. Many chemotherapeutics activate programmed cell death and it is thought that mitochondrial dysfunction may be one mechanism by which cancer cells evade killing by these compounds. Screening the metabolic profiles of ovarian cancer cell lines and patient ascites-derived tumor cells reveals that ovarian cancers fall into unique bioenergetic subgroups. For example, Ovarian Clear Cell Carcinomas (OCCC) display high oxygen consumption rate and glycolytic flux compared to the more common high grade serous adenocarcinoma (HGSA) subtype. In addition, we show that a portion of HGSAs have severe mitochondrial dysfunction, that is marked by a decrease in mitochondrial respiration, a lack of response to the uncoupler FCCP and a concomitant reliance on alternate metabolic pathways. Moreover, this is accompanied by enhanced chemoresistance to Cisplatin and Taxol. The cause of mitochondrial dysfunction has been attributed to a number of factors, including deregulation in mitochondrial fission/fusion dynamics. Moreover, fission is an integral component of apoptotic and authophagy pathways. Interestingly, the observed HGSA mitochondrial dysfunction correlates with aberrant fusion/fission dynamics and expression of a low molecular weight variant of the mitochondrial fission protein Drp1. The potential significance of Drp1 in ovarian cancer etiology is highlighted by TCGA data, where more than 15% of HGSA samples display significant increases in Drp1 mRNA levels, and associated amplification of the Drp1 gene DNM1L. Whether this represents the shorter, potentially dominant-negative Drp1 variant identified in our work is currently under active investigation. Our data suggest that compromised mitochondrial function and fission/fusion dynamics may be a hallmark of a previously unidentified subgroup of highly chemoresistant EOCs and that this is associated with aberrant expression of the fission protein Drp1. Studies are underway to identify the molecular identity and regulation of short Drp1, and the mechanistic links to alterations in fission, metabolic switching and chemoresistance. Citation Format: Dong-Hui Shin, Usawadee Dier, Patrick F. Timmins, Joshua Kesterson, Rebecca Phaeton and Nadine Hempel. MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-059.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".