RESUMEN

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.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Tumores Neuroendocrinos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Heterogeneidad Genética , Humanos , Neoplasias Pulmonares/metabolismo , Ratones Noqueados , Tumores Neuroendocrinos/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Análisis de la Célula Individual , Carcinoma Pulmonar de Células Pequeñas/metabolismo