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

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. Single-cell RNA sequencing from a single human SCLC biopsy from the liver.