Abstract A63: Clonal analysis of normal and malignant human mammary epithelial cell responsiveness to radiation
Notice bibliographique
Résumé
Abstract Knowledge gap: Fatal breast cancers are characterized by biological, genomic and extensive treatment heterogeneity. Although many breast cancers can now be cured by established therapies, treatment failure remains a major problem and is difficult to predict. In the current era of “personalized medicine”, a possible solution is to develop a large-scale system for quantifying responses to candidate treatments of individual malignant human mammary cells with in vivo clonogenic activity. Such cells can be detected by their ability to produce uniquely barcoded clones of progeny in xenografted immunodeficient mice and the clones obtained can be assessed for their size and number using next generation sequencing of tumor extracts. However, to pursue this approach it is first critical to establish how the clone content of a tumor may vary according to the number or type of competent tumorigenic and/or other cells that are present in the inoculum used to initiate tumor formation, and hence whether and how these parameters may influence assessment of the treatment responsiveness of these cells. Approach/methods: Here we describe the development and initial testing of a method to measure the treatment responsiveness of large numbers of tumorigenic cells using radiation as a prototypic treatment. Treatment sensitivity of in vitro colony-forming cells (CFCs) will then be compared with future measurements of in vivo clone-initiating tumorigenic cells obtained by sequencing the progeny of DNA-barcoded input cells. Results: In an initial series of experiments we showed that normal human luminal progenitor (LP) CFCs are ~1.5-fold more radioresistant than basal cell (BC) CFCs, and both are more sensitive than either type of mouse mammary CFCs. In vitro CFC assays of 2 human breast cancer cell lines (MDA MB231 and SUM149, with in vitro CFC frequencies of 70% and 40%, respectively) showed these to be 1.2- and 1.5-fold more radioresistant than normal LPs. Limiting dilution analysis showed the corresponding frequency of in vivo tumor-initiating cells in these 2 cell lines to be 1/6 and 1/47. Assessment of their response to radiation is complicated by the finding that the barcoded clone content of tumors initiated with >20,000 of these cells (untreated) is inversely related to the number injected and, at these input cell doses, very heterogeneous clone dynamics are also seen in successive passages. However, evidence of a positive linear cell dose-clone yield relationship is seen at input transplants of <1,000 cells from these 2 lines and this relationship would be predicted to extend to initial transplants of <2-5,000 cells. Recently we have found that normal human mammary LPs and BCs transduced with KRASG12D generate tumors efficiently in immunodeficient mice. Thus a next step is to determine if and how the radiosensitivity of the tumorigenic cells changes during the transformation process. Conclusion: These results highlight the complex clonal dynamics already operative in the growth of tumorigenic cells present in relatively homogeneous established human mammary cell lines and set the stage for future measurements of clone yields from irradiated cells derived from mammary tumors of different origins. Citation Format: Sneha Balani, Nagarajan Kannan, Long V. Nguyen, Sylvain Lefort, Davide Pellacani, Connie J. Eaves. Clonal analysis of normal and malignant human mammary epithelial cell responsiveness to radiation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A63.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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) | 0,000 | 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 tête enseignante, 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 ».