Fig. 2: Indisulam resistance is associated with cell state switch from ADRN to MES and melanocytic state in human MYCN-amplified neuroblastomas.
From: RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity
a Individual tumor volume for SJNB14 PDXs implanted in CB17/SCID mice undergoing repeated cycles (2 weeks as one cycle) of treatment with vehicle (n = 5) and 25 mg/kg indisulam (n = 5), 5 days on, two ways off. Note: relapsed tumors after the 4th cycle were re-implanted to new mice before the 5th cycle treatment due to the aging of the primary mice. GSEA shows the ADRN (b) and hypoxia (c) gene signatures are significantly downregulated in resistant tumors vs. naïve tumors, while the interferon (d) gene signature is significantly upregulated. Nominal p-values are calculated by one-sided Fisher’s exact test. e Heatmap showing that the expression changes of melanocytic markers, Wnt ligands, MES, and ADRN transcriptional factors in naïve (biological replicates n = 2) vs. resistant tumors (biological replicates n = 2). The z-score-based heatmap after log2-transformed expression is generated by using the SRplot program. f The expression of melanocytic markers and Wnt ligands in a human neuroblastoma cohort (TARGET study)21. The expression scale bar indicates z-score based heatmap after log2-transformed expression. g Log2 transformed RBM39 expression from normalized RNA-seq in naïve vs. resistant SJNB14 tumors (biological replicates n = 2). h Volcano plot shows the differential peaks of H3K27Ac in naïve vs. resistant tumors by CUT&Tag analysis. Y-axis = −log10 transformed p values, x-axis = log2 transformed fold changes. P-value is calculated by the Benjamini-Hochberg method. i IGV plots show the peak changes of at the loci of TWIST1, PHOX2B, and S100B. j GSEA shows the upregulation of H3K27Ac at the genomic loci of MES TFs. Nominal p-values are calculated by one-sided Fisher’s exact test. k GSEA shows the downregulation of H3K27Ac at the genomic loci of ADRN signature genes. Nominal p-values is calculated by one-sided Fisher’s exact test. Source data are provided as a Source Data file.
