Abstract B005: BMP signaling determines neuroblastoma sensitivity to retinoic acid by directing cell fate
Notice bibliographique
Résumé
Abstract Retinoic acid (RA) is a standard-of-care neuroblastoma drug used during post-chemo consolidation therapy. Based on clinical trials from the 90s, RA benefits 10-15% of patients. It is widely believed the anti-cancer activity of RA is due to retinoid-induced differentiation of cancer cells, conclusions largely attributable to observations in cell culture. However, given RA is typically used in the minimal residual disease setting, this mechanism has never been definitively proved in patients. To better understand RA’s activity, we deployed several new technologies. First, we conducted genome-wide CRISPR modifier screens in RA-treated hyper-sensitive neuroblastoma cell lines. Surprisingly, we found that, in these cells, RA primarily decreased cell viability via apoptosis or senescence, rather than differentiation—activities in which the CRISPR screens strongly implicated bone morphogenetic protein (BMP) signaling. Using ChIP-seq and RNA-seq we showed these behaviors were mediated by the coordinated gene regulatory actions of RARA and BMP-family SMAD transcription factors. Notably, interactions between BMP signaling and RA are well established in developmental biology, where BMP signaling can tip cell fate decisions between differentiation, apoptosis, and senescence upon exposure to naturally occurring RA, behaviors that can seemingly be maintained in neuroblastoma cells. Next, we assessed the correlations between RA IC50 and the expression of all (∼20,000) genes in a panel of 19 cell lines. Remarkably, SMAD9, a critical downstream transcription factor of the BMP pathway, was the #1 most correlated gene with RA IC50 (R = -0.92, P = 4.2 × 10-6), suggesting a highly generalizable relationship between BMP signaling and RA response. By modulating SMAD9, or other components of BMP signaling, we could promote apoptosis/senescence and sensitize cells to RA. We then performed large-scale drug combination screens of RA and the drug FK506, which can amplify BMP signaling activity. RA exhibited a synergistic effect with FK506 in all 10 neuroblastoma cell lines we tested, very strikingly in some cases, suggesting it could be possible to pharmacologically amplify the activity of RA in patients. Finally, using published single-cell RNA-seq data from neuroblastoma patient samples, we found BMP signaling activity is relatively low in primary tumors, but much higher in disseminated metastatic neuroblastoma cells in the bone marrow. We confirmed this trend using immunofluorescence staining in 6 paired primary patient samples. This site-specific variability in BMP signaling activity provides the first reasonable explanation for RA’s curious clinical activity, whereby it has little effect on bulky established tumors, but has been shown to clear disseminated metastatic cells from the bone marrow during consolidation therapy. Overall, our study revealed that BMP signaling controls neuroblastoma cell fate and sensitivity to RA and that this observation is consistent with the unique clinical behaviors of this drug. Citation Format: Min Pan, Yinwen Zhang, William C. Wright, Hyeong-Min Lee, Richard H. Chapple, Xueying Liu, Jonathan Low, Duane Currier, Allister J. Loughran, Michael A. Dyer, Shondra M. Pruett, Burgess Freeman III, Taosheng Chen, Brian J. Abraham, Elizabeth Stewart, John Easton, Paul Geeleher. BMP signaling determines neuroblastoma sensitivity to retinoic acid by directing cell fate [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B005.
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 | 0,001 | 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) | 0,006 | 0,002 |
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 ».