Fig. 1
A causal regulatory network of small cell lung cancer identifies GRN as a key regulator of chemo-resistant signatures. A Overlap of network neighbors of chemo-resistance signature genes. EP resistant signatures derived from a PDX model (EP res) and cisplatin resistant signatures derived from a mouse model (Cisplatin res) were projected on the network with the signatures as seed nodes and their n-layer neighbors in the network were collected Gene: direct overlap of signature genes without network expansion, 1: overlap of one-layer neighboring nodes from seeds, 2: overlap of two-layer neighboring nodes from seeds, 2c: overlap of the largest connected subnetwork among the two-layer neighboring nodes, 3: overlap of three-layer neighboring nodes from seeds. The bin colors indicate odd ratio (OR) of the overlap between EP res and Cisplatin res associated gene sets. Fisher’s exact test (FET) p-values were -log10 transformed. B The largest connected subnetworks of the two-layer neighboring nodes of Ep res (left) and Cisplatin res (right). The intersected subnetwork is highlighted (middle). C A subnetwork within two layers from GRN. EP res and cisplatin res genes are colored in red and purple, respectively. D–F Correlation between GRN expression in SCLC cell lines (x-axis) and IC50 values (y-axis) to SCLC drugs (cisplatin, oxaliplatin, and irinotecan) downloaded from GDSC database [6]. Ln(IC50) zero value corresponding to 1 µM is marked in red dashed line. G Correlation between GRN expression (x-axis) and the ranking of EP response (y-axis) in 19 SCLC PDX models [3]. D–G Pearson correlation coefficients and p-values are calculated. H GRN expression (y-axis) difference between baseline and progressed tumors from SCLC CDX [7]. I Grn expression (y-axis) difference between neuroendocrine and non-NE SCLC cells from Rb1f/f;Trp53f/f; Ptenf/f TKO GEMM [8]. H–I Two-sided t-test p-value is calculated to assess the differences. J GRN expression (y-axis) between vehicle- and cisplatin-treated CDX models from patients SC68 and SC53 [9], respectively. Expression differences are assessed by Wilcoxon rank-sum test. K (Above) Western blots showing protein expression of GRN in four SCLC cell lines. (Below) Viability of each cell lines with equimolar treatment of EP for 96-h relative to vehicle control. IC50 = ~ 18.83uM and ~ 1.86uM for SHP77 and H841, and ~ 55 nM and ~ 0.54 nM for H524 and H2081, respectively. L, M (Above) Western blots confirming GRN over-expression (OE) in the two GRNlow cells (H524 and H2081). (Below) Viability of each cell line with equimolar treatment of EP for 96-h relative to vehicle control. IC50 > 1uM for both H524 and H2081 with GRN OE