Fig. 6: YAP1 promotes the transdifferentiation of SCLC cells to a non-neuroendocrine fate.

a Schematic representation of neuroendocrine (NE) and non-NE SCLC cells isolated from the TKO;Hes1^GFP/+ mouse model for ATAC-seq. b Volcano plot of differentially accessible peaks from the ATAC-seq data comparing non-NE SCLC cells to NE SCLC cells (significant peaks with more than 2-fold change and p-adj value < 0.001 are in red). Wald test with Benjamini–Hochberg correction. c Scatterplot showing the enriched motifs identified by HOMER analysis on the more open peaks in non-NE SCLC cells (significant motifs with more than 1.5-fold change and p-value < 0.001 are in red). d Expression of Hippo pathway members and targets from RNA-seq data in GFP^high cells compared to GFP^neg cells (n = 4). Error bars, log2 fold change estimate ± SE. e–g, e Representative brightfield images of NE mouse KP1 SCLC cells 14 days after Ctrl-GFP (control) or YAP1-GFP overexpression. Scale bar, 100 μm. Quantification of the number of adherent cells counted per well of a 6-well plate (f) and the percentage of cells that became adherent (g) as in (e) (n = 3 independent experiments). Unpaired t-test, data represented as mean ± s.d. h Immunoassay of non-NE and NE markers in KP1 cells after overexpression of either Ctrl-GFP or YAP1-GFP (4 weeks). Bands of two molecular weights are detected with the antibody against YAP1 due to some incomplete cleavage of P2A. Samples from n = 2 independent experiments. i Volcano plot of differentially expressed genes from RNA-seq data of 5 days overexpression of YAP1 in KP1 cells. Notch2, Hes1, Rest and Hippo pathway members are highlighted (significant genes with more than 2-fold change and p-adj value < 0.05 are in red). Wald test with Benjamini–Hochberg correction. j ChIP-qPCR analysis of YAP1 binding at the promoters of Pou2f1 (negative ctrl), Ctgf (positive ctrl) and Notch2 in independently generated GFP^high cell lines from TKO;Hes1^GFP/+ mouse SCLC tumors (n = 3). Unpaired t-test, data represented as mean ± s.d. See also Supplementary Fig. 9 and Supplementary Data 12 and 13. Source data are provided as a Source Data file.