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

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

PROVIDER: PRJNA716967 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14061549.fastq.gz	Fastqsanger.gz
	SRR14061550.fastq.gz	Fastqsanger.gz
	SRR14061551.fastq.gz	Fastqsanger.gz
	SRR14061552.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

ASCL1 represses a SOX9<sup>+</sup> 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 osteosarcoma and chondroid tumors, whose propensity is impacted by cell of origin. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1 and represses genes involved in the Hippo/Wnt/Notch developmental pathways in vivo. Importantly, ASCL1 represses a SOX9/RUNX1/RUNX2 program in vivo and SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Together, in a MYC-driven SCLC model, ASCL1 promotes neuroendocrine fate and represses the emergence of a SOX9+ nonendodermal stem-like fate that resembles neural crest.

| S-EPMC8168563 | biostudies-literature

ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin [RNA-Seq]

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 cell types. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation, but surprisingly converts tumors to a SOX9+mesenchymal/neural-crest-stem-like state that has the capacity to differentiate into RUNX2+bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation. Here we perform bulk RNA sequencing on RPMA tumor samples to compare gene expression patterrns with RPM tumors with intact ASCL1.

2021-05-22 | GSE155691 | GEO

ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin [ChIP-Seq]

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 cell types. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation, but surprisingly converts tumors to a SOX9+ mesenchymal/neural-crest-stem-like state that has the capacity to differentiate into RUNX2+bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation. Here, we perform ChIP on RPM tumors against ASCL1, NEUROD1, and H3k27Ac to view binding profiles and identify target genes of ASCL1 and NEUROD1.

2021-05-22 | GSE155690 | GEO

Effect of SOX9 depletion on transcription mRNA in hESC-derived cranial neural crest cells [SLAM-seq]

Project description:To assess the effects of SOX9 depletion on transcription in hESC-derived cranial neural crest cells, we performed genome editing of the H9 hESC lines to tag SOX9 with FKBPV36, V5, and mNeonGreen. Upon differentiating edited hESC to cranial neural crest cells using an established protocol, addition of the degrader molecule dTAGV-1 results in SOX9 depletion. We then profiled transcription by metabolic labeling of RNA (SLAM-Seq) in undepleted CNCCs or CNCCs in which SOX9 was depleted for 3h or 24h

2022-07-04 | GSE205903 | GEO

ChIP-seq on Olig2, Ascl1, Tcf3, Max, NFI, Sox2, Sox9 and Sox21 in mouse neural stem cells

Project description:Definition of genome wide binding profile of Olig2, Ascl1, Tcf3, Max, NFI, Sox2, Sox9 and Sox21 in mouse neural stem cells. Three sets of processed data files, together with a README file (README_E-MTAB-2228.docx) describing the source and content of each file, are provided as additional files to this ArrayExpress submission and can be found in https://www.ebi.ac.uk/arrayexpress/files/E-MTAB-2228 .

2014-09-19 | E-MTAB-2228 | biostudies-arrayexpress

Effect of SOX9 dosage changes on chromatin accessibility in hESC-derived cranial neural crest cells [ATAC-seq]

Project description:To assess the effects of quantitative SOX9 dosage changes on chromatin accessibility in hESC-derived cranial neural crest cells, we performed genome editing of the H9 hESC lines to tag SOX9 with FKBPV36, V5, and mNeonGreen. Upon differentiating edited hESC to cranial neural crest cells using an established protocol, addition of differing concentrations of the degrader molecule dTAGV-1 results in different SOX9 concentrations, as measured by flow cytometry. We then profiled chromatin accessibility in each of these SOX9 concentrations

2022-07-04 | GSE205900 | GEO

Effect of SOX9 dosage changes on gene expression in hESC-derived cranial neural crest cells [RNA-seq]

Project description:To assess the effects of quantitative SOX9 dosage changes on gene expression in hESC-derived cranial neural crest cells, we performed genome editing of the H9 hESC lines to tag SOX9 with FKBPV36, V5, and mNeonGreen. Upon differentiating edited hESC to cranial neural crest cells using an established protocol, addition of differing concentrations of the degrader molecule dTAGV-1 results in different SOX9 concentrations, as measured by flow cytometry. We then profiled gene expression profiling in each of these SOX9 concentrations

2022-07-04 | GSE205902 | GEO

Effect of SOX9 depletion on active chromatin marks in hESC-derived cranial neural crest cells [ChIP-seq]

Project description:To assess the effects of SOX9 depletion on active chromatin marks in hESC-derived cranial neural crest cells, we performed genome editing of the H9 hESC lines to tag SOX9 with FKBPV36, V5, and mNeonGreen. Upon differentiating edited hESC to cranial neural crest cells using an established protocol, addition of the degrader molecule dTAGV-1 results in SOX9 depletion. We then profiled the active chromatin mark H3K27ac by ChIP-Seq in undepleted CNCCs or CNCCs in which SOX9 was depleted for 3h or 24h. We also titrated SOX9 to four distinct levels with dTAGV-1 and assessed SOX9 binding by V5 ChIP-seq, as well as TWIST1 and TFAP2A binding by ChIP-seq.

2022-07-04 | GSE205901 | GEO

miR-302 is a temporal regulator of neural crest development [Mouse miRNA-seq]

Project description:We analyzed wildtype and miR-302 knockout embryos at E7.5 and sorted neural crest using Wnt1-Cre at E8.5 and Sox9 at E9.5 to capture miRNA differences during neural crest development

2020-03-09 | GSE137240 | GEO

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