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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]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE149179 | GEO | 2020/05/28

REPOSITORIES: GEO

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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.

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

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