Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

SUBMITTER: Olsen RR

PROVIDER: S-EPMC8168563 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

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+ neural-crest-stem-like state in small cell lung cancer

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

| PRJNA716967 | ENA

Small molecule-mediated reprogramming of Xenopus blastula stem cells to a neural crest state

Project description:Here we describe and validate a protocol for small molecule-mediated induction of the neural crest state as a new tool for generating this important cell type and facilitating future studies of its development.

2023-10-13 | GSE230350 | GEO

Epigenetic Editing of Ascl1 Gene in Neural Stem Cells by Optogenetics.

Project description:Enzymes involved in epigenetic processes such as methyltransferases or demethylases are becoming highly utilized for their persistent DNA or histone modifying efficacy. Herein, we have developed an optogenetic toolbox fused to the catalytic domain (CD) of DNA-methyltransferase3A (DNMT3A-CD) or Ten-Eleven Dioxygenase-1 (TET1-CD) for loci-specific alteration of the methylation state at the promoter of Ascl1 (Mash1), a candidate proneuron gene. Optogenetical protein pairs, CRY2 linked to DNMT3A-CD or TET1-CD and CIB1 fused to a Transcription Activator-Like Element (TALE) locating an Ascl1 promoter region, were designed for site specific epigenetic editing. A differentially methylated region at the Ascl1 promoter, isolated from murine dorsal root ganglion (hypermethylated) and striated cells (hypomethylated), was targeted with these optogenetic-epigenetic constructs. Optimized blue-light illumination triggered the co-localization of TALE constructs with DNMT3A-CD or TET1-CD fusion proteins at the targeted site of the Ascl1 promoter. We found that this spatiotemporal association of the fusion proteins selectively alters the methylation state and also regulates gene activity. This proof of concept developed herein holds immense promise for the ability to regulate gene activity via epigenetic modulation with spatiotemporal precision.

| S-EPMC5299429 | biostudies-literature

Snail2 directly represses cadherin6B during epithelial-to-mesenchymal transitions of the neural crest.

Project description:The neural crest, a transient population of migratory cells, forms the craniofacial skeleton and peripheral nervous system, among other derivatives in vertebrate embryos. The transcriptional repressor Snail2 is thought to be crucial for the epithelial-to-mesenchymal transition (EMT) that promotes neural crest delamination from the neural tube; however, little is known about its downstream targets. To this end, we depleted avian Snail2 in the premigratory neural crest using morpholino antisense oligonucleotides and examined effects on potential targets by quantitative PCR. Several dorsal neural tube genes were upregulated by alleviating Snail2 repression; moreover, the cell adhesion molecule cadherin6B was derepressed within 30 minutes of blocking Snail2 translation. Examination of the chick cadherin6B genomic sequence reveals that the regulatory region contains three pairs of clustered E boxes, representing putative Snail2 binding sites. Furthermore, in vivo and in vitro biochemical analyses demonstrate that Snail2 directly binds to these sites and regulates cadherin6B transcription. These results are the first to describe a direct target of Snail2 repression in vivo and in the context of the EMT that characterizes neural crest development.

| S-EPMC2595139 | biostudies-literature

Distinct molecular profile and restricted stem cell potential defines the prospective human cranial neural crest from embryonic stem cell state.

Project description:Neural crest cells are an embryonic multipotent stem cell population. Recent studies in model organisms have suggested that neural crest cells are specified earlier than previously thought, at blastula stages. However, the molecular dynamics of early neural crest specification, and functional changes from pluripotent precursors to early specified NC, remain to be elucidated. In this report, we utilized a robust human model of cranial neural crest formation to address the distinct molecular character of the earliest stages of neural crest specification and assess the functional differences from its embryonic stem cell precursor. Our human neural crest model reveals a rapid change in the epigenetic state of neural crest and pluripotency genes, accompanied by changes in gene expression upon Wnt-based induction from embryonic stem cells. These changes in gene expression are directly regulated by the transcriptional activity of β-catenin. Furthermore, prospective cranial neural crest cells are characterized by restricted stem cell potential compared to embryonic stem cells. Our results suggest that human neural crest induced by Wnt/β-catenin signaling from human embryonic stem cells rapidly acquire a prospective neural crest cell state defined by a unique molecular signature and endowed with limited potential compared to pluripotent stem cells.

| S-EPMC7932500 | biostudies-literature

MAPK pathway activation selectively inhibits ASCL1-driven small cell lung cancer.

Project description:Activation of mitogenic signaling pathways is a common oncogenic driver of many solid tumors including lung cancer. Although activating mutations in the mitogen-activated protein kinase (MAPK) pathway are prevalent in non-small cell lung cancers, MAPK pathway activity, counterintuitively, is relatively suppressed in the more aggressively proliferative small cell lung cancer (SCLC). Here, we elucidate the role of the MAPK pathway and how it interacts with other signaling pathways in SCLC. We find that the most common SCLC subtype, SCLC-A associated with high expression of ASCL1, is selectively sensitive to MAPK activation in vitro and in vivo through induction of cell-cycle arrest and senescence. We show strong upregulation of ERK negative feedback regulators and STAT signaling upon MAPK activation in SCLC-A lines. These findings provide insight into the complexity of signaling networks in SCLC and suggest subtype-specific mitogenic vulnerabilities.

| S-EPMC8528729 | biostudies-literature

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

Slug and Sox9 cooperatively determine the mammary stem cell state.

Project description:Regulatory networks orchestrated by key transcription factors (TFs) have been proposed to play a central role in the determination of stem cell states. However, the master transcriptional regulators of adult stem cells are poorly understood. We have identified two TFs, Slug and Sox9, that act cooperatively to determine the mammary stem cell (MaSC) state. Inhibition of either Slug or Sox9 blocks MaSC activity in primary mammary epithelial cells. Conversely, transient coexpression of exogenous Slug and Sox9 suffices to convert differentiated luminal cells into MaSCs with long-term mammary gland-reconstituting ability. Slug and Sox9 induce MaSCs by activating distinct autoregulatory gene expression programs. We also show that coexpression of Slug and Sox9 promotes the tumorigenic and metastasis-seeding abilities of human breast cancer cells and is associated with poor patient survival, providing direct evidence that human breast cancer stem cells are controlled by key regulators similar to those operating in normal murine MaSCs.

| S-EPMC3305806 | biostudies-literature

Gingivae contain neural-crest- and mesoderm-derived mesenchymal stem cells.

Project description:Gingivae represent a unique soft tissue that serves as a biological barrier to cover the oral cavity side of the maxilla and mandible. Recently, the gingivae were identified as containing mesenchymal stem cells (GMSCs). However, it is unknown whether the GMSCs are derived from cranial neural crest cells (CNCC) or the mesoderm. In this study, we show that around 90% of GMSCs are derived from CNCC and 10% from the mesoderm. In comparison with mesoderm MSCs (M-GMSCs), CNCC-derived GMSCs (N-GMSCs) show an elevated capacity to differentiate into neural cells and chondrocytes and induce activated T-cell apoptosis in vitro. When transplanted into mice with dextran sulfate sodium (DSS)-induced colitis, N-GMSCs showed superior effects in ameliorating inflammatory-related disease phenotype in comparison with the M-GMSC treatment group. Mechanistically, the increased immunomodulatory effect of N-GMSCs is associated with up-regulated expression of FAS ligand (FASL), a transmembrane protein that plays an important role in MSC-based immunomodulation. In summary, our study indicates that the gingivae contain both neural-crest- and mesoderm-derived MSCs with distinctive stem cell properties.

| S-EPMC3744273 | biostudies-other