Abstract 4774: Adaptation to chronic oxidative stress promotes metabolic rewiring to maintain redox balance in HER2+ breast tumors
Notice bibliographique
Résumé
Abstract Breast cancer is the most commonly diagnosed malignancy in women worldwide. Breast tumors possess a high degree of intra- and inter-tumoral heterogeneity, enabling the emergence of aggressive, therapy-resistant tumors. One contributor to breast tumor heterogeneity is reactive oxygen species (ROS), which are unstable oxygen-containing molecules that modify proteins, lipids, and DNA. Our lab has developed unique models of HER2+ breast cancer that evolved in vivo under conditions of low (ROSLOW) and high (ROSHIGH) chronic oxidative stress to acquire more aggressive properties. As such, we became interested in understanding the underlying mechanisms by which breast cancer cells capitalize on sustained oxidative stress to acquire more aggressive properties. We show that, relative to their parental and ROSLOW counterparts, ROSHIGH-evolved tumors are better able to maintain redox balance by coping with ROS-induced damage in vivo and following H2O2 treatment in vitro. Moreover, ROSHIGH-evolved breast cancer cells lose their aggressive phenotype in vitro, implying a necessary microenvironmental contribution. RNAseq analysis of parental and aggressive breast cancers further identified glycolytic and hypoxic transcriptional signatures that were preferentially induced in breast cancers that adapted to chronic oxidative stress. Therefore, we hypothesized that breast cancer cells conditioned to cope with chronic oxidative stress may re-wire their glucose metabolism to support ROS buffering, which may be facilitated by a hypoxic tumor microenvironment. Notably, ROSHIGH-evolved tumors are insensitive to inhibition of glycolysis using 2-deoxyglucose (2-DG); however, we show that they are specifically sensitized to inhibition of glutathione synthesis, and this sensitivity is exacerbated when treated in combination with 2-DG. As well, we show through glucose tracing that ROSHIGH-evolved tumors exhibit increased incorporation of glucose-derived carbons into glutathione. This data confirms that breast tumor adaptation to chronic oxidative stress promotes metabolic re-wiring to support ROS scavenging. To begin interrogating the role hypoxia plays in this phenotype, we assessed cell proliferation and levels of hypoxia-responsive genes following hypoxia exposure in our breast cancer models in vitro. Relative to their parental counterparts, breast cancer cells that adapted to chronic oxidative stress exhibit enhanced proliferation in hypoxia and are better able to upregulate hypoxia-responsive genes, even in response to modest changes in oxygen levels. Overall, our study shows that tumor adaptation under chronic oxidative stress promotes metabolic rewiring which may be facilitated by a hypoxic microenvironment. Citation Format: Caitlynn Nicole Mirabelli, Rachel La Selva, Matthew Annis, Ouafa Najyb, Steven Hébert, Claudia Kleinman, Julie St-Pierre, Peter Siegel, Josie Ursini-Siegel. Adaptation to chronic oxidative stress promotes metabolic rewiring to maintain redox balance in HER2+ breast tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4774.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».