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ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE155692 | GEO | 2021/05/22

REPOSITORIES: GEO

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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

ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin

Project description:ASCL1 represses a latent osteogenic program in small cell lung cancer in multiple cells of origin

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

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

| PRJNA655227 | ENA

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

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

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ASCL1 represses a SOX9<sup>+</sup> neural crest stem-like state in small cell lung cancer.

Project description: Not available

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Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma.

Project description: Not available

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Nkx2.1 represses a latent gastric differentiation program in lung adenocarcinoma

Project description:During cancer evolution, cellular differentiation programs become dysregulated. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to study the fate of lung epithelial cells upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also gastric transdifferentiation. Nkx2-1 maintains pulmonary identity by sequestering the Foxa1 transcription factor at lung-specific loci and inhibiting Foxa1 binding to gastrointestinal targets. Murine Nkx2-1-negative lung tumors mimic the mucinous subtype of human lung adenocarcinoma, which also exhibits gastric transdifferentiation. Nkx2-1-negative lung adenocarcinomas are dependent on the gastrointestinal gene Hnf4a for efficient initiation. Thus, loss of Nkx2-1 results in transdifferentiation rather than stable dedifferentiation in vivo, suggesting that inactivation of both active and latent differentiation programs may be required for tumors to reach a primitive, dedifferentiated state. The study was designed to compare the expression profiles of Nkx2-1-positive lung adenocarcinomas with tumors in which Nkx2-1 was deleted at the time of initiation or 6-7 months after initiation.

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Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma

Project description:Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to study the fate of lung epithelial cells upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also gastric transdifferentiation. Nkx2-1 maintains pulmonary identity by sequestering the Foxa1 transcription factor at lung-specific loci and by inhibiting Foxa1 binding to gastrointestinal targets. Murine Nkx2-1-negative lung tumors mimic the mucinous subtype of human lung adenocarcinoma, which also exhibits gastric transdifferentiation. Nkx2-1-negative lung adenocarcinomas are dependent on the gastrointestinal gene Hnf4a for efficient initiation. Thus, loss of Nkx2-1 causes transdifferentiation rather than stable dedifferentiation in vivo, suggesting that inactivation of both active and latent differentiation programs are required for tumors to reach a primitive, dedifferentiated state. ChIP-seq data from murine lung adenocarcinomas on (i) transcription factors Nkx2-1 and Foxa in Nkx2-1-deleted tumors and Nkx2-1-positive control tumors, and (ii) four histone marks in Nkx2-1-deleted tumors and Nkx2-1-positive control tumors. (All samples in duplicate and with input controls, i.e. (2 x [(3+3) + (2+8)]) - 1 = 31 samples total - 1 input control used for transcription factor and histone mark, GSM1059357)

2013-04-09 | E-GEOD-43252 | biostudies-arrayexpress

Nkx2.1 represses a latent gastric differentiation program in lung adenocarcinoma

2013-04-10 | GSE36473 | GEO