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Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor
Chunhui Jiang, … , Chao Xing, Lu Q. Le
Chunhui Jiang, … , Chao Xing, Lu Q. Le
Published May 4, 2023
Citation Information: J Clin Invest. 2023;133(12):e168227. https://doi.org/10.1172/JCI168227.
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Research Article Oncology Article has an altmetric score of 3

Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor

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Abstract

Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall downregulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-β1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-β1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA sequencing, we found that immune cells including macrophages and T cells produce TGF-β1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-β1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as biomarkers for disease diagnosis and treatment response.

Authors

Chunhui Jiang, Ashwani Kumar, Ze Yu, Tracey Shipman, Yong Wang, Renee M. McKay, Chao Xing, Lu Q. Le

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Figure 1

Plexiform neurofibroma development is characterized by ECM enrichment.

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Plexiform neurofibroma development is characterized by ECM enrichment.
(...
(A) Representative images showing spinal cords extracted from wild-type (WT) mice (n = 3) and H7;Nf1mut mice, which develop plexiform neurofibroma (pNF) (n = 4). The pNF spinal cord shows enlarged dorsal root ganglia (DRGs), indicating pNF formation. (B) Volcano plot of the mass spectrometry data set showing P values against fold changes (fc). The red line indicates P value equal to 0.05, and targets above the red line are significantly changed. (C–E) Gene Ontology (GO) analysis showing the top 10 significantly upregulated categories in cellular component (C), molecular function (D), and biological pathway (E) in pNF compared with WT. The left y axis indicates the level of significance of each category. FDR, false discovery rate. The right y axis indicates the number of targets included in each category. (F) Mass spectrometry data analysis for the indicated collagen isoforms based on the abundance ratios. Data are presented as means ± SEM. Comparisons among groups were performed by Student’s t test. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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