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KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer (atac batch2)

ABSTRACT: Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1,POU2F3, and Inflammatory. Initially SCLC subtypes were thought to be mutually exclusive, butrecent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes.Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTXinactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express bothASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in anactive chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as \an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE215827 | GEO | 2023/06/08

REPOSITORIES: GEO

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KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer (scatac)

Project description:Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1,POU2F3, and Inflammatory. Initially SCLC subtypes were thought to be mutually exclusive, butrecent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes.Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTXinactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express bothASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in anactive chromatin state with its loss increasing H3K27me3 near their promoters leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as \an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.

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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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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.

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