Abstract 21: p66ShcA is a contextual breast cancer metastasis promoter or suppressor depending on the tumor microenvironment
Notice bibliographique
Résumé
Abstract Introduction: Src homology and collagen A (ShcA) adaptor proteins are essential during breast cancer progression. However, the role of the largest isoform, p66ShcA, is conflicting and still poorly understood. Under high levels of stress p66ShcA is phosphorylated on serine36, within its CH2 domain, allowing it to translocate to the mitochondria and induce the formation of reactive oxygen species (ROS) to promote apoptosis. Previously, we provided the first in vivo evidence that p66ShcA can influence both pro and anti-tumorigenic functions in ErbB2+ luminal breast cancer. Stable overexpression of p66ShcA reduced tumor outgrowth while simultaneously elevating the expression of mesenchymal genes to promote tumor plasticity. In this study, we evaluated the role of p66ShcA in metastatic dissemination to the lung in a model of basal breast cancer, which typically is associated with poor outcome. Hypothesis: p66ShcA regulates basal breast cancer metastasis to the lung. Methods: Screening a panel of basal breast cancer cells in vivo selected to the lung, liver and bone, we found p66ShcA enriched in lung and liver metastatic variant cell lines relative to parental breast cancer cells and those in vivo selected through the mammary fatpad. Using CRISPR/Cas technology we genetically deleted p66ShcA and rescued with p66ShcA-WT or a p66ShcA-S36A mutant. Lung metastatic basal breast cancer cells were injected into the fourth gland of the mammary fatpad. Tumors were measured using calipers 3 times/week following first palpation (>50mm3) followed by surgical resection to monitor the lung metastatic burden. In addition, we performed tail vein injections to monitor lung metastatic burden following direct entry into the circulation. Results: Loss of p66ShcA significantly reduced the metastatic burden to the lung following surgical tumor resection and this reduction was partially rescued by stable overexpression of wild type (WT), but not S36A mutated p66ShcA from the primary site. These effects were not due to altered anti-oxidant expression levels, changes in oxidative DNA Damage or microvessel density. Intriguingly, we found that WT-rescue of p66ShcA significantly elevated the migratory speed of breast cancer cells in vitro and corroborates our in vivo metastatic burden data. However, this is in stark contrast to our tail vein data, where WT-rescue of p66ShcA significantly inhibited lung metastasis. Conclusion: p66ShcA is required for efficient metastasis to the lung in a mitrochondrial-ROS-dependent fashion from the primary site. Our data suggest that cues from the tumor microenvironement of the mammary fatpad are essential for successful colonization and outgrowth at oxygen rich sites, such as the lung, as breast cancer cells with elevated expression of p66ShcA directly entering the circulation suppressed lung metastatic burden. Citation Format: Jesse Hudson, Kyle Lewis, Julien Senécal, Alexander Kiepas, Sébastien Tabariès, Valérie Sabourin, Ryuhjin Ahn, Rachel La Selva, Peter Siegel, Giuseppina Ursini-Siegel. p66ShcA is a contextual breast cancer metastasis promoter or suppressor depending on the tumor microenvironment [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 21.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,001 |
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 ».