Small cell lung cancer (SCLC) is a recalcitrant malignancy defined by subtypes on the basis of differential expression of the ASCL1, NEUROD1, and POU2F3 transcription factors. The MUC1-C protein is activated in pulmonary epithelial cells by exposure to environmental carcinogens and promotes oncogenesis; however, there is no known association between MUC1-C and SCLC. We report that MUC1-C is expressed in classic neuroendocrine (NE) SCLC-A, variant NE SCLC-N and non-NE SCLC-P cells and activates the MYC pathway in these subtypes. In SCLC cells characterized by NE differentiation and DNA replication stress, we show that MUC1-C activates the MYC pathway in association with induction of E2F target genes and dysregulation of mitotic progression. Our studies further demonstrate that the MUC1-C!MYC pathway is necessary for induction of (i) NOTCH2, a marker of pulmonary NE stem cells that are the proposed cell of SCLC origin, and (ii) ASCL1 and NEUROD1. We also show that the MUC1-C!MYC!NOTCH2 network is necessary for self-renewal capacity and tumorigenicity of NE and non-NE SCLC cells. Analyses of datasets from SCLC tumors confirmed that MUC1 expression in single SCLC cells significantly associates with activation of the MYC pathway. These findings demonstrate that SCLC cells are addicted to MUC1-C and identify a potential new target for SCLC treatment. Implications: This work uncovers addiction of SCLC cells to MUC1-C, which is a druggable target that could provide new opportunities for advancing SCLC treatment.
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