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Epigenetic and genetic change through cell cycling under selumetinib treatment

ABSTRACT: Epigenetic and genetic change through cell cycling under selumetinib treatment

PROVIDER: PRJNA877852 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21484500.fastq.gz	Fastqsanger.gz
	SRR21484501.fastq.gz	Fastqsanger.gz
	SRR21484502.fastq.gz	Fastqsanger.gz
	SRR21484503.fastq.gz	Fastqsanger.gz
	SRR21484504.fastq.gz	Fastqsanger.gz

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Project description:Neurofibromatosis Type I is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, mitogen -activated protein kinase inhibitor. The purpose of this study is to analyze the transcriptome of cNF tumors before and after selumetinib treatment to both understand tumor composition and response. We obtained biopsy sets of tumors both pre- and post- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced a total of 5,844 nuclei and identified 30,442 genes in the untreated group and sequenced 5,701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified populations of Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells and calculated their frequencies in both groups. While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ after treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat. Together they indicate that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These gene signatures and interaction pathways suggest they might be a key determinate for response.

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Epigenetic and genetic change through cell cycling under selumetinib treatment

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