Abstract A003: ASAP1 regulates myogenic differentiation in rhabdomyosarcoma by modulating YAP localization
Notice bibliographique
Résumé
Abstract Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. RMS is thought to arise due to defective differentiation in skeletal muscle precursor cells. Differentiation-inducing therapy may improve outcomes for RMS patients with advanced disease. In RAS-mutant PAX fusion-negative RMS (FN-FMS), targeting ERK1/2 activation through MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival in preclinical studies. However, the duration of therapeutic response is short lived. Identifying additional targets for differentiation therapy is necessary. We propose that ASAP1, an Arf GTPase-activating protein (Arf GAP) highly expressed in FN-RMS and implicated in breast and colorectal cancer progression as well as osteogenic and retinal endothelium differentiation, contributes to FN-RMS differentiation. We find that knockdown (KD) of ASAP1 inhibits differentiation in myoblasts and FN-RMS cells, and its overexpression enhances differentiation. Moreover, myogenic differentiation-associated genes are not enriched upon loss of ASAP1. We discover that KD of ASAP1 homologs, ASAP2 and ASAP3, also blocks differentiation. However, loss of a paralogous Arf GAP, ARAP1, does not, indicating that ASAP regulates differentiation through a mechanism not explained by GAP activity alone. Interestingly, KD of Arf1 or Arf5, small GTPases inactivated by ASAP, also blocks differentiation of FN-RMS, suggesting a novel relationship between Arf and ASAP. Using RNAseq, qPCR, and immunoblotting techniques, we show that loss of ASAP blocks myogenic transcription factor expression. To determine the mechanism by which ASAP1 regulates myogenic transcription factor expression, we investigate the PI3K/AKT, MAPK, and Hippo pathways, which are known to be regulated by ASAP1. While the PI3K/AKT and MAPK pathways are unaffected, downstream components of the Hippo pathway are modulated by ASAP1 KD in FN-RMS cells treated with MEKi. YAP and TAZ are transcriptional coactivators that promote proliferation. Upon Hippo pathway activation, YAP/TAZ activity is blocked by phosphorylation at a nuclear exclusion site. Using cell fractionation and immunoblotting techniques, we find that induction of differentiation by MEKi increases TAZ phosphorylation, excluding it from the nucleus and blocking pro-proliferative transcription. Further, upon ASAP1 KD, TAZ phosphorylation is blocked, restoring nuclear localization, and inhibiting MEKi-induced differentiation. In conclusion, we discover that ASAP1 regulates MEKi-induced differentiation of FN-RMS cells by modulating TAZ localization and supports targeting the YAP pathway as a strategy for FN-RMS differentiation therapy. Our work also identifies ASAP1 as a potential effector of Arf1 activity, a novel interaction of these two proteins. The results described herein provide a deeper understanding of differentiation in FN-RMS and establish the groundwork for advancing differentiation therapy in FN-RMS. Citation Format: Katie E. Hebron, Olivia Feehan-Nelson, Angela Kim, Xiaoying Jian, Sofia A Girald, Paul Randazzo, Marielle E. Yohe. ASAP1 regulates myogenic differentiation in rhabdomyosarcoma by modulating YAP localization [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A003.
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) | 0,003 | 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 ».