Abstract A12: Regulation of the mitochondrial stress response and metabolism by the intraperitoneal tumor environment during ovarian cancer transcoelomic metastasis
Bibliographic record
Abstract
Abstract Transcoelomic metastasis represents one of the routes by which ovarian cancer cells colonize the omental tissues of the intraperitoneal (IP) cavity. Large quantities of viable tumor cells and spheroid aggregates can be isolated from ascites of advanced stage ovarian cancer patients, suggesting that cancer cells spend some time in anchorage independence under the physical and chemical influence of the IP tumor environment. Using ovarian cancer cell lines and patient ascites-derived tumor cells we demonstrate that levels of the mitochondrial stress response proteins, superoxide dismutase 2 (Sod2) and the deacetylase sirtuin 3 (SIRT3), are significantly increased when cultured in anchorage independent conditions, where cells rapidly form spheroid aggregates. Mimicking the ascites fluid current we show that expression of these proteins is further enhanced when spheroids are exposed to sheer forces, suggesting that the physical environment influences cellular stress adaptation. Presently, the combination of these physical cues and chemical stimuli emanating from ascites fluid are being interrogated in the co-regulation of the above mitochondrial proteins, focusing on the role of redox modulators and metabolite composition of ascites. It is our hypothesis that this stress response adaptation not only aids survival of cells in anchorage independence, but that it also drives a metabolic regulatory switch. Anchorage independent spheroids display a slowing in glycolysis and an increase in mitochondrial respiratory reserve capacity, as assessed by extracellular flux analysis. Sod2 expression is required for maintaining this mitochondrial respiratory function by scavenging damaging superoxide anion. Further, we observe decreases in global and mitochondrial acetylation, suggesting that deacetylase activity may be increased in spheroids. SIRT3 is a direct regulator of Sod2 activity, and is an important sensor of nutrient stress and modulator of metabolism, including the stimulation of fatty acid oxidation by deacetylation and activation of long-chain-specific acyl-CoA dehydrogenase. It has previously been demonstrated that metastatic ovarian cancer cells rely on fatty acid oxidation given their propensity to colonize the lipid-rich environments of the omentum. Studies are under way to test the hypothesis that SIRT3 expression stimulated by the IP tumor environment during anchorage independence primes ovarian cancer cells for fatty acid oxidation and is a necessary step before the colonization of the omentum. Citation Format: Dong-Hui Shin, Victoria Jones, Sara Shimko, Usawadee Dier, Trevor Shepherd, Timmins Patrick, Nadine Hempel. Regulation of the mitochondrial stress response and metabolism by the intraperitoneal tumor environment during ovarian cancer transcoelomic metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A12.
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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 | 0.000 | 0.000 |
| 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 | 0.000 |
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".