Classical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer

Comprehensive genomic analyses of small cell lung cancer (SCLC), the most aggressive form of lung cancer, have revealed near universal loss of tumor suppressors (RB1 and TP53) and frequent genomic amplification of all three MYC family members. The amplification of each Myc family member is mutually exclusive; hence it had been long suggested that they are functionally equivalent. However, their expression has more recently been associated with specific neuroendocrine markers and distinct histopathology. In this study, we explored a novel role of c-Myc and L-Myc as lineage determining factors contributing to SCLC molecular subtypes and histology. Integrated analyses of a gene regulatory network generated from mRNA expression of primary SCLC tumor and chromatin state profiling of SCLC cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein the L-Myc signature was enriched for neuronal pathways while the c-Myc signature was enriched for Notch signaling and epithelial-to-mesenchymal transition. We investigated the functional redundancy and distinction of c-Myc and L-Myc, and noted the insufficiency of L-Myc to induce lineage switch in contrast to the potential of c-Myc to induce trans-differentiation. c-Myc rewires the Myc-accessible landscape and activates neuron al repressor, Rest to mediate transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, our findings reveal a previously undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses.