Abstract 4730: ASCL1 activates neuronal stem cell-like lineage programming through the remodeling of the chromatin landscape in prostate cancer
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".