a, Schematic of patient clinical courses, including the time points at which blood was collected for CDX generation (red triangles). Solid and dashed bars indicate treatment and are drawn to scale. tx, treatment. b, Histological images of leptomeningeal disease detected in the brain of MDA-SC39 (arrow) at different magnifications (top), including characterization of standard SCLC markers (bottom). The presence of leptomeningeal disease was detected in one of five mice whose brains were examined. Scale bars: 1 mm (left), 100 µm (top right) and 10 µm (bottom right). CHGA, chromogranin A; NCAM, neural cell adhesion molecule; SYP, synaptophysin; TTF1, thyroid transcription factor-1. c, Waterfall plot of the maximum change in tumor from baseline following the treatment of CDXs with cisplatin. MDA-SC4s, MDA-SC39s, MDA-SC68s and HCI-008s were platinum sensitive, while MDA-SC16r, MDA-SC49r, MDA-SC55r and MDA-SC75r were platinum resistant (see legend to the right of f). d, Schematic showing the method for performing single-cell RNA-Seq on CDXs with individual cell clusters indicated on in the t-SNE visualization on the right. e, t-SNE analysis of eight CDXs. Cells from each CDX were more similar to themselves than to other models. f, Violin plots indicating the range of expression of NCAM1, SYP, CHGA and NKX2-1 (TTF1) in single cells from each CDX. Each dot represents one cell and the violin curves represent the density of cells at different expression levels. g, Expression patterns of ASCL1, NEUROD1, POU2F3 and YAP1 genes within each CDX. h, t-SNE feature plots showing the heterogeneity of expression of MYC, MYCL and MYCN in all CDXs (identified by the color coding in e). In e–g, n = 2,000 cells.