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MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [SuperSeries]

ABSTRACT: MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [SuperSeries]

PROVIDER: PRJNA627594 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11594404.fastq.gz	Fastqsanger.gz
	SRR11594405.fastq.gz	Fastqsanger.gz
	SRR11594406.fastq.gz	Fastqsanger.gz
	SRR11594407.fastq.gz	Fastqsanger.gz
	SRR11594408.fastq.gz	Fastqsanger.gz

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MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [Human SCLC biopsy]

Project description:Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. We developed an in vitro model of MYC-driven SCLC tumor cell progression, and performed a time-series analysis of single-cell transcriptome profiling to reveal that MYC drives the dynamic evolution of SCLC subtypes. Analyses of these single-cell RNA seq data reveal that MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. Additional single-cell RNA sequencing of 4RPM tumors reveal individual tumors to consist of cells at nearly every stage of RPM tumor evolution modeled in vitro. With the single-cell RNA sequencing of this human SCLC liver biopsy, along with IHC on a panel of 21 human biopsies, we show that human SCLC exhibits intratumoral SCLC subtype heterogeneity, suggesting this dynamic evolution occurs in patient tumors. Together, these single-cell RNA sequencing data support our conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

2020-05-28 | GSE150766 | GEO

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [WGS data]

Project description:Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. To study transcriptional dynamics of MYC-driven tumor evolution and compare transcriptional states to human SCLC tumors, we performed bulk and single-cell RNA-sequencing on various timepoints of Rb1/Trp53/MycT58A (RPM) tumor cells (from Ad-Cgrp-Cre infected mice) as they progress in culture, and on RPM bulk tumors. Here, to complement these analyses we performed ~30X whole-genome sequencing (WGS) of early (day 4) and late (day 23) time-point RPM tumor cells from culture, along with a matching normal blood control to confirm complete loss of expected regions of Rb1 and Trp53. WGS analyses revealed no detectable copy number variations (CNVs), and SNV analysis suggests that minimal clonal and subclonal evolution occurs in vitro. Together, these data ultimately reveal that MYC drives the dynamic evolution of SCLC subtypes. We find that MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. These findings support our overall conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

2020-05-28 | GSE149444 | GEO

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [Bulk RNA-seq of RPM and RPR2 tumors]

Project description:Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. We perform bulk RNA-sequencing on SCLC tumors from RPM and Rb1/Trp53/Rbl2 (RPR2) GEMMs, initiated by CGRP-Cre, to complement time-series analysis of single-cell transcriptome profiling and reveal that MYC drives the dynamic evolution of SCLC subtypes. MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. Sequenced RPM tumors driven by MycT58A, in comparison to RPR2 tumors associated with high Mycl, have increased intratumoral subtype heterogeneity by bulk-seq, single-cell RNA seq, and IHC compared to RPR2 tumors. In RPM tumors with high MYC, tumors are able to proceed to non-NE subtypes resembling the NEUROD1+ and YAP1+ human SCLC subtypes. These findings support our overall conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

2020-05-28 | GSE149175 | GEO

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [SuperSeries]

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-05-28 | GSE149180 | GEO

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [Bulk RNA-seq of RPM time-series cells]

Project description:Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. To study transcriptional dynamics of MYC-driven tumor evolution and compare transcriptional states to human SCLC tumors, we performed bulk RNA-sequencing on various timepoints of Rb1/Trp53/MycT58A (RPM) tumor cells (from Ad-Cgrp-Cre infected mice) as they progress in culture. These bulk RNA-seq data of the RPM time-series cells complement time-series analysis of single-cell transcriptome profiling of similar timepoints and ultimately reveal that MYC drives the dynamic evolution of SCLC subtypes. We find that MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. These findings support our overall conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

2020-05-28 | GSE149178 | GEO

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [Single Cell RNA seq on RPM time-series cells and 4 RPM bulk tumors]

Project description:Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. Here, we develop an in vitro model of MYC-driven SCLC tumor cell progression and perform a time-series analysis of single-cell transcriptome profiling to reveal that MYC drives the dynamic evolution of SCLC subtypes. Analyses of these single-cell RNA seq data reveal that MYC promotes a temporal shift from an Ascl1-to-Neurod1-to-Yap1+ state from a neuroendocrine cell of origin. They also support our findings that MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. Additional single-cell RNA sequencing of 4 bulk Rb1/Trp53/MycT58A (RPM) tumors reveal individual tumors to consist of cells at nearly every stage of RPM tumor evolution modeled in vitro. Together, these single-cell RNA sequencing data place 3 of 4 SCLC subtypes on a defined trajectory and suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

2020-05-28 | GSE149179 | GEO

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [WGS data]

Project description:MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [WGS data]

| PRJNA628698 | ENA

MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [Human SCLC biopsy]

Project description:MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate [Human SCLC biopsy]

| PRJNA633536 | ENA

MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate.

Project description:Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use mouse and human models with a time-series single-cell transcriptome analysis to reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits intratumoral subtype heterogeneity, suggesting that this dynamic evolution occurs in patient tumors. These findings suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

| S-EPMC7393942 | biostudies-literature

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (scRNA-Seq)

Project description:Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy escape in multiple cancer types. The temporal transcriptional changes of this process remain largely undefined. Here, we performed a multi-omics time course analysis of our pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells. With integrative analyses of RNA sequencing and ATAC sequencing, a shared developmental trajectory is identified among all transformed patient samples. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 and ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. Lastly, TFAP4 and ASCL1/2 feedback were identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, and normal neuroendocrine cells.

2023-11-24 | GSE240056 | GEO

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