Abstract C35: The development of metastatic mouse models of neuroblastoma to bone and brain to identify the molecular mechanisms governing metastasis
Notice bibliographique
Résumé
Abstract Metastasis is a key reason for the lack of success in treating children with neuroblastoma (NB). Over 50% of patients present with metastatic lesions in the bone, brain, liver and lymph nodes, with a high fatality rate for patients that relapse with those metastases. A better understanding of the molecular processes defining the complexity and multi-step nature of NB dissemination is required for the development of effective treatments. To date, there is no NB model that quantitatively and reproducibly metastasizes to bone and brain. Thus, we developed novel metastatic mouse models of neuroblastoma to bone and brain through in vivo selection to enhance metastatic capability. SK-N-AS, derived from a bone marrow metastasis, and IMR-32, a MYCN-amplified line derived from an abdominal mass, were tagged for in vivo monitoring using a triple reporter (TR) encoding TK, GFP and firefly luciferase, which allows for nuclear imaging, FACs analysis, and whole body bioluminescence. Reporter expression was confirmed by double sorting for GFP and testing for luciferase activity. Cells were introduced into the blood stream of NOD/SCID mice through intra-cardiac injection, and monitored bi-weekly using bioluminescence. SK-N-ASTR cells metastasized to the adrenal gland (87%, 13/15 animals) and bone (mandible, hindlimbs, 67%, 10/15 animals), whereas IMR-32TR cells metastasized to bone (100%, 10/10 animals) and brain (40%, 4/10 animals). Metastatic lesions were confirmed by ex-vivo bioluminescence, 3D bioluminescence, MRI or micro-CT. Cells from specific metastatic sites of individual mice were isolated, expanded in culture, GFP sorted and injected into a second cohort of mice. Several of the SK-N-ASTR re-injected cell lines derived from bone exhibited enhanced metastasis after one round of in vivo selection, with 100% metastasis to bone and the adrenal gland (a common location of primary NB tumours) and up to 60% metastasis to brain, as confirmed by MRI. Subsequently, these animals had a decreased overall survival rate of approximately 43 days relative to the parental cell line, of 69 days. The metastatic sub-populations do not proliferate at higher rates than the parental cell line, as assessed by BrdU labeling. Thus, the enhanced metastasis observed in vivo is not due to a faster growth rate, but rather selection of metastasis promoting functions. This is supported by the finding that the metastatic SK-N-ASTR sub-populations also exhibited enhanced migration and invasion toward serum, as assessed using boyden chambers, compared to the parental line. These sub-populations are being characterized to identify the molecular mechanisms governing metastasis. Metastasis to brain and bone is an often fatal event in children with newly diagnosed and recurrent NB. We have developed the first reproducible and efficient NB metastatic mouse model to identify novel genes and signalling proteins regulating metastasis, and to identify drug candidates that suppress metastatic growth. Citation Format: Kelly E. Fathers, Samar Mouaaz, Constanza Rioseco, Anna Mourskaia, Ronald Blasberg, Meredith Irwin, Peter Siegel, David Kaplan. The development of metastatic mouse models of neuroblastoma to bone and brain to identify the molecular mechanisms governing metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C35.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,002 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».