Abstract B32: ASAP1 regulates differentiation in myoblasts and PAX-FOXO1 fusion-negative rhabdomyosarcoma
Notice bibliographique
Résumé
Abstract Rhabdomyosarcoma (RMS), the most frequently diagnosed soft-tissue sarcoma in children, is caused by a differentiation defect in skeletal muscle precursor cells. Despite aggressive, multimodal therapies, the prognosis for recurrent PAX-FOXO1 fusion-negative RMS (FN-RMS) remains poor. Inducing differentiation in diseases defined by defective differentiation programs has led to curative therapies in cancers such as acute promyelocytic leukemia. A recent study showed that inducing differentiation slowed tumor growth and extended survival in a xenograft model of FN-RMS, identifying differentiation as a promising therapeutic target in FN-RMS. However, genes associated with differentiation are frequently found to be hijacked by tumor cells and repurposed for proinvasive programs. Therefore, better understanding of differentiation signaling and its relation to invasion could reveal novel therapeutic opportunities for patients with advanced FN-RMS. We hypothesize that ASAP1, an Arf GTPase-activating protein implicated in differentiation in normal cells and invasion in carcinoma, promotes progression by controlling proinvasive elements of differentiation signaling through focal adhesion assembly. ASAP1, an Arf GTPase-activating protein (Arf GAP), regulates integrin adhesion complexes, critical regulators of biologic processes such as proliferation, migration, and differentiation that are commonly dysregulated in cancer. ASAP1 is overexpressed in several cancers and correlates with increased metastasis and poor patient prognosis but has also been shown to promote differentiation. The mechanisms by which ASAP1 affects cancer progression and differentiation and the relationship between these effects are not yet understood. We found that ASAP1 is overexpressed in FN-RMS. ASAP1 overexpression inhibits proliferation in myoblasts, but not in FN-RMS. Knockdown of ASAP1 inhibits differentiation in both myoblast and FN-RMS cell lines, while overexpression enhances differentiation. Moreover, gene set enrichment analysis shows that myoblast differentiation-associated genes fail to become enriched upon knockdown of ASAP1. Finally, knockdown of Arf1 and Arf5, established binding partners of ASAP1, also blocks differentiation of FN-RMS cell lines, indicating that ASAP1 may regulate differentiation through its interaction with Arf GTPases. These data support our hypothesis that ASAP1 regulates the continuum of differentiation and invasion in FN-RMS. As a continuing test of the hypothesis, future studies will investigate focal adhesion assembly, dynamics, and signaling, which are processes known to be affected by ASAP1, as a mechanism for ASAP1-mediated regulation of myoblast differentiation. Citation Format: Katie E. Hebron, Olivia Feehan-Nelson, Xiaoying Jian, Sofia A. Girald, Paul A. Randazzo, Marielle E. Yohe. ASAP1 regulates differentiation in myoblasts and PAX-FOXO1 fusion-negative rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B32.
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 | 0,001 |
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 ».