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ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [RNA-Seq]

ABSTRACT: Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and divergent differentiation toward neuroendocrine lineage. We found that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identified motifs for the proneuronal transcription factor ASCL1 to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPI governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse the neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183199 | GEO | 2022/03/30

REPOSITORIES: GEO

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ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [ChIP-Seq]

Project description:Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and divergent differentiation toward neuroendocrine lineage. We found that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identified motifs for the proneuronal transcription factor ASCL1 to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPI governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse the neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.

2022-03-30 | GSE183198 | GEO

ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [ATAC-Seq]

2022-03-30 | GSE183196 | GEO

FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [ChIP-seq]

Project description:In castration-resistant prostate cancer, lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the NEPC phenotype, driving neuroendocrine differentiation. However, ASCL1’s influence on neuronal lineage switching and maturation, as well as its partners in NEPC, remain largely unknown. Here, we provided insights into ASCL1’s cistrome reprogramming in ARPI-induced NEPC versus terminal NEPC and showed that ASCL1 binding pattern tailors the subsequent expression of transcription factor combinations that underlie discrete terminal NEPC identity. We identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC that it is highly expressed in ASCL1-driven NEPC. FOXA2 and ASCL1 interact and work in concert to orchestrate terminal neuronal differentiation in prostate cancer, and regulate key neuroendocrine-associated genes including PROX1. Our findings provide insights into the molecular conduit underlying the interplay between different lineage determinant transcription factors to support the neuroendocrine identity in prostate cancer.

2024-10-23 | GSE273956 | GEO

FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [RNA-seq]

2024-10-23 | GSE273957 | GEO

Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (ChIP-seq)

Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors ChIP-seq analysis performed on three ASCL1high and two NEUROD1high human SCLC cell lines to identify ASCL1 and/or NEUROD1 binding sites in these two types of cells. Also, we performed ChIP-seq for Ascl1 binding sites in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.

2016-07-21 | E-GEOD-69394 | biostudies-arrayexpress

Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (RNA-seq)

Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors RNA-seq analysis performed on two ASCL1high and two NEUROD1high human SCLC cell lines to identify gene expression patterns in these cells. Also, we performed RNA-seq in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.

2016-07-21 | E-GEOD-69393 | biostudies-arrayexpress

Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer [RNA-seq]

Project description:Small cell lung cancer (SCLC) frequently harbors mutually exclusive genomic amplification of MYC family members. Therefore, it has been long suggested that they are functionally equivalent; however, more recently, their expression has been associated with specific neuroendocrine markers and distinct histopathology. Integrated transcriptomic and epigenomic analyses showed that c-Myc and L-Myc impart neuronal and non-neuroendocrine associated transcriptional programs, respectively, both associated with distinct SCLC lineage. Genetic replacement of c-Myc with L-Myc in c-Myc-SCLC induced a neuronal state but was insufficient to induce ASCL1 lineage. In contrast, c-Myc induced transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, we characterize an undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses.

2020-12-31 | GSE156328 | GEO

Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer [ATAC-seq]

2020-12-31 | GSE156333 | GEO

ASCL1 represses a SOX9+ neural-crest-stem-like state in small cell lung cancer

Project description:ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9+ mesenchymal/neural-crest-stem-like state and the emergence of bone and more rarely, cartilaginous tumors. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1, and represses regulators of Hippo, Wnt and Notch developmental pathways in vivo. ASCL1 also represses SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Here, we utilize single-cell RNA sequencing to capture transcriptomic signatures of RPM (Rb1/Trp53/Myc), RPR2 (Rb1/Trp53/Rbl2), and RPMA (Rb1/Trp53/Myc/Ascl1) GEMM tumors to support our conclusion that in MYC-driven SCLC, ASCL1 promotes neuroendocrine fate and represses the emergence of SOX9+ non-endodermal stem-like or mesenchymal fates. These data were integrated with 4 additional invasive RPM tumors from NCBI GEO: GSE149180.

2021-05-22 | GSE169529 | GEO

Prostate adenocarcinoma transition to neuroendocrine small cell tumors requires ASCL1

Project description:Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-indifferent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the transition to NEPC suggests a model of lineage plasticity, where AR-dependent luminal tumors progress towards an AR-independent neuroendocrine (NE) lineage. Genetic analysis of human NEPC showed a frequent loss of RB1 and TP53, and in experimental models, loss of both genes facilitates the transition to a NE lineage. Transcriptomics has shown the lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we used genetically engineered mouse models harboring Cre induced loss of Rb1 and Trp53 with MycT58A overexpression (RPM), to model prostate adenocarcinoma with NEPC by establishing prostate organoids that are subsequently used to generate subcutaneous allograft tumors. These tumors are heterogeneous and display adenocarcinoma, squamous, and NE features. ASCL1 and NEUROD1 are expressed within the NE defined regions, with ASCL1 being more predominant than NEUROD1. Genetic loss of ASCL1 in this model does not decrease tumor growth or tumor formation, however, there is a notable decrease in NE identity and an increase in cells with basal-like cell identity. This study provides a new in vivo model to study the progression of prostate cancer to NEPC and establishes the requirement for ASCL1 in driving neuroendocrine differentiation.

2024-08-28 | GSE264598 | GEO

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