Abstract 2443: Oxygen metabolism and hypoxia tolerance in organoid models of pancreatic ductal adenocarcinoma
Bibliographic record
Abstract
Abstract Background: Pancreatic Ductal Adenocarcinoma (PDAC) has extremely heterogeneous hypoxic microenvironments across patients and high levels of hypoxia are correlated with increased tumor aggressiveness and resistance to therapy. However, the underlying genetic contributors to variations in hypoxia and its importance to the disease is currently unknown. We hypothesize that genetic mutations in PDAC associated with two principal factors - oxygen metabolism and hypoxia tolerance - influence the steady state levels of hypoxia in individual tumors. The demand for oxygen, which is influenced by genetic driven changes in cellular metabolism, define the levels and steepness of hypoxia gradients around perfused vessels. Tolerance to hypoxia determines the time tumor cells can survive in severe microenvironments depleted of oxygen and other nutrients. Both factors are affected by the activation of adaptive hypoxia stress response pathways including the HIF, UPR, and autophagy pathways. Method: We developed patient-derived-organoids from PDAC tumors for in vitro studies of oxygen metabolism and glycolytic rates using the Seahorse XF96. We also characterized hypoxia tolerance through monitoring of organoid growth and secondary growth under defined levels of oxygenation. In addition, we have developed an immunofluorescence image analysis pipeline to evaluate in vivo oxygen demand/consumption through the quantification of oxygen and proliferation gradients around perfused blood vessels. Results: We observed significant heterogeneities in oxygen metabolism and hypoxia tolerance across our patient derived organoid models. We also demonstrated the importance of PERK/UPR pathway in mediating both oxygen metabolism and hypoxia tolerance through regulation of ULK1, a kinase involved in the initiation of autophagy. Inhibition or knockdown of ULK1 decreased cell survival and correspondingly sensitized cells to hypoxia in organoid and tumor models. This is accompanied by accumulation of mitochondria and a corresponding increase in oxygen consumption, resulting in increased development of hypoxic cells. Conclusion: These experiments demonstrate the dual importance of oxygen metabolism and hypoxia tolerance and set the stage for the evaluation of these parameters and identification of the underlying genetic drivers of the hypoxic microenvironment. These genetic markers would be used for patient-selection and development of hypoxia-targeted therapies. Citation Format: Ji Zhang, Qingquan Liu, Dan Cojocari, Mark Zaidi, Trevor McKee, Nikolina Radulovich, Ming-Sound Tsao, David Hedley, Marianne Koritzinsky, Bradly G. Wouters. Oxygen metabolism and hypoxia tolerance in organoid models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2443.
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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 | 0.001 |
| 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 | 0.001 |
| 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".