Abstract A34: Hypoxia signaling pathway is frequently involved in pediatric osteosarcoma microenvironment, as diagnostic and prognostic biomarkers, but also as new therapeutic targets
Bibliographic record
Abstract
Abstract Osteosarcoma is the first bone cancer diagnosed in adolescent and young adults. Multiple studies involved a deregulation of osteoblast, osteoclast, or microenvironment genes in their development and progression. Nevertheless, no focus was already done in the oxygen-modulated environment of those cancers. Our objectives in this study were to determine, first, the presence of hypoxia deregulation in a cohort of pediatric osteosarcomas (pOS at diagnosis) and in 4 PDCLs (patient-derived cell lines from diagnostic samples). For this purpose, we performed CGHarray for 67 samples and a validation by semiquantitative PCR in another cohort of 20 samples. We also explored by immunohistochemistry in 30 tumor specimens protein expressions of key biomarkers from the hypoxic signaling pathway. Those biomarkers were validated and assessed functionally by immunofluorescence and Western blotting in PDCLs and paired xenografts. All those results in the pOS collections were correlated to survivals and response to first-line therapies. Secondly, the role of hypoxia modulation in PDCLs was determined using variations of oxygen levels from 21% to 5% on cell proliferation characteristics and protein parameters. Finally, to understand how the process of hypoxia is a potential target for pOS treatment, we inhibited different targets of the mTor/HIF1alpha pathway in those PDCLs. As expected, the hypoxia signaling pathway was highly expressed in pOS (tumor samples and PDCLs). Several biomarkers (for example, ULK1, USP33, VEGFR2, CCL7, etc.) were overexpressed in specific groups, linking them significantly to prognosis and a response to chemotherapy. Most of them were involved in the metabolism, autophagy, or angiogenic processes. The PDCLs also expressed in vitro and in xenografts several proteins of this hypoxic pathway as in tumors themselves (pS6, phosphor-mTor, pAKT, HIF1alpha, HIF2alpha). The induction of HIF1alpha during oxygen decrease is early and constant in PDCLs. mTor and HIF2alpha were not induced by the variation of oxygen and were constantly expressed in the cells. Surprisingly, most of the PDCLs increase their proliferation rate in hypoxic conditions, but do not change their microscopic aspects. Finally, the inhibition of mTor and HIF1alpha with rapamycine and irinotecan, respectively, decreases the cell proliferation with a complete inhibition of the targets. In conclusion, hypoxia seems to be frequently involved in pOS through different downstream signaling processes and might be a new potential way of treatment. Citation Format: Marina Pierrevelcin, Audrey Grain, Aurelien Tripp, Adeline Obrecht, Benoit Lhermitte, Noelle Weingertner, Nathalie Gaspar, Pascal Villa, Isabelle Lelong-Rebel, Françoise Redini, Monique Dontenwill, Natacha Entz-Werlé. Hypoxia signaling pathway is frequently involved in pediatric osteosarcoma microenvironment, as diagnostic and prognostic biomarkers, but also as new therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A34.
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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".