Abstract 4730: ASCL1 activates neuronal stem cell-like lineage programming through the remodeling of the chromatin landscape in prostate cancer
Notice bibliographique
Résumé
Abstract Introduction: Second-generation AR pathway inhibitors such as Enzalutamide (ENZ) are highly effective in treating castration-resistant prostate cancer (CRPC). However, they play an important role in the emergence of AR-independent phenotypes, including treatment-induced neuroendocrine prostate cancer (tNEPC). Few genetic differences are observed between CRPC and tNEPC, suggesting an epigenetic dysregulation underlining this conversion. Method: To capture the evolution of CRPC to tNEPC, we measured changes in chromatin accessibility of CRPC cells upon exposure to ENZ and in tNEPC cell lines via ATACseq. We performed RNAseq from matched cell lines. We conducted ASCL1, H3K27me3 and EZH2 ChIPseq. Multi-omic analysis were performed integrating RNAseq, ATACseq, ChIPseq, RNA and protein expression. Result: We identified the motif of the transcription factor ASCL1 becoming accessible as early as 3 days, with continued enrichment at 10 days post ENZ-treatment and in NEPC cell-lines. ASCL1 expression and activity are significantly upregulated in NEPC cell lines and patient tumors. Using our unique model of tNEPC, we showed that knockdown of ASCL1 causes extensive chromatin reorganization leading to reduced expression of neuronal and plasticity markers and overall abolishment of the NEPC program. Loss of ASCL1 dysregulated Polycomb repressor complex 2 activity (loss of H3K27 methylation) via di-association of complex due to phosphorylation of EZH2 at T311 resulting in loss of EZH2 binding to the chromatin and likely cause of the H3K27 demethylation. Cell fractionation and confocal microscopy combined with ChIPseq data confirmed loss of EZH2 binding to the chromatin. We identified that loss of ASCL1, phenocopying EZH2 inhibition, reactivated luminal programming and potentially re-sensitizing tNEPC cells to further AR targeted therapies. Altogether, suggests that ASCL1 may drive early transcriptional and epigenetic reprogramming through the PRC2, facilitating the emergence and maintenance of tNEPC. Conclusion: Our research provides the centrality of epigenetic reprogramming in driving the uprising of a plastic phenotype in response to AR pathway inhibition and provides insight into the role of ASCL1 in early drug-induced epigenomic plasticity that supports this reprogramming toward androgen independence. We report that ASCL1 modulates the chromatin dynamics to support a plastic lineage by influencing neuronal stem cell-like regulatory networks. In the treatment-resistant, high plasticity state, inhibition of ASCL1 reverses the lineage to an epithelial-luminal state, providing potential for targeting these highly aggressive tumors. This work provides much-needed insight into ASCL1 function and dependency that together nominates ASCL1 as a bona fide clinical target. Citation Format: Shaghayegh Nouruzi, Dwaipayan Ganguli, Nakisa Tabrizian, Maxim Kobelev, Olena Sivak, Takeshi Namekawa, Alastair Davies, Amina Zoubeidi. ASCL1 activates neuronal stem cell-like lineage programming through the remodeling of the chromatin landscape in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4730.
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) | 0,005 | 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 ».