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

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. [Display omitted] •Multiple SCLC molecular subtypes arise from a neuroendocrine cell of origin•MYC drives the NEUROD1+ and YAP1+ subtypes of SCLC in a temporal evolution•MYC directly activates NOTCH signaling to reprogram neuroendocrine fate•Multiple SCLC molecular subtypes are present within individual human tumors Ireland et al. show that MYC activates Notch signaling to dedifferentiate neuroendocrine small cell lung cancer (SCLC) in a conserved trajectory from ASCL1+ to NEUROD1+ to YAP1+ non-neuroendocrine subtypes, suggesting that these are not distinct subtypes but different stages of progressive evolution of SCLC.