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. 2022 Jul 14;5:697. doi: 10.1038/s42003-022-03654-9

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Schematic of workflow used to identify compensatory pathways in SHH xenograft tumors following MEK inhibitor treatment. A portion of this schematic, including mouse, syringe, and cell icon images, was created with BioRender.com. b Representative H&E images of FFPE sections from control (left) and selumetinib-treated (right) UI226 SHH MB xenografts. Scale bars: 1500 μm (upper) and 600 μm (lower). c Volcano plot depicting the log2 fold change and p-values in RNA-seq data with points in red identifying the 576 significantly differentially expressed genes (FDR < 0.05). d Normalized counts for representative differentially expressed transcripts from RNA-seq data. IFIT2 (p = 6.33E–16), IGFN1 (p = 0.0002), RIMBP2 (p = 0.00049) and JAK2 (p = 0.0041) are increased while CD271 (p = 0.047) expression is decreased in selumetinib-treated UI226 SHH MB xenografts relative to vehicle controls. p < 0.05 *, p < 0.01**, p < 0.001***. Expression differences were calculated using the DESeq results function. Differentially expressed genes were identified using a q-value (Benjamini-Hochberg corrected p-value) cut-off of 0.05, which coincides with a p-value of 0.00168. e GSEA demonstrating that genes associated with a downregulated MEK signature, increased JAK/STAT3, TNFalpha, and apoptosis signaling are enriched in genes sets that are upregulated in selumetinib-treated xenografts. padj < 0.05* for all signatures. f Most significantly downregulated genes in selumetinib-treated xenografts. Differentially expressed genes were identified using a q-value (Benjamini-Hochberg corrected p-value) cut-off of 0.05, which coincides with a p-value of 0.00168. padj < 0.05* for all genes. g Representative images of IHC staining for pSTAT3 (Tyr705) in FFPE sections from two independent control (upper) and selumetinib-treated (lower) UI226 SHH MB xenografts. Scale bar: 150 μm. h Quantitative analyses of IHC pSTAT3 (Tyr705) staining in vehicle control (white) and selumetinib-treated (blue) xenografts. The proportion of pSTAT3+ cells for each sample was calculated using QuPath and expressed as the total number of pSTAT3+ cells relative to the total number of cells in each image (pSTAT3- nuclei (hematoxylin-stained) and pSTAT3+ cells). Significance was calculated using a two-tailed t-test. Error bars: SEM. p = 0.011.