Expression of MUC1 in SCLC tumor tissues. A, Analysis of the GSE60052 SCLC bulk RNA-seq dataset demonstrating significant correlations of MUC1 with MYC and NOTCH2 expression in SCLC tumor tissues. B, Analysis of the GSE138267 SCLC scRNA-seq dataset demonstrating MUC1 expression in clusters of SCLC cells obtained from seven patient-derived CDX models. C, Distribution of MUC1 expression in the seven CDX models. D, Significant associations of MUC1 expression with activation of the HALLMARK MYC TARGETS V1 pathway in individual tumors. E, Representative IHC staining of MUC1-C expression in SCLC tumor tissue. Bar represents 50 μm. F, Proposed model for MUC1-C in driving SCLC progression. MUC1-C activates MYC and E2F target genes that contribute to the RSR and mitotic progression. MUC1-C→MYC signaling also drives expression of NOTCH2 and NE dedifferentiation. MUC1-C thereby integrates activation of the dysregulated MYC and E2F pathways and RSR with NE dedifferentiation, stemness, and self-renewal in SCLC cells.