PRC2 loss drives MPNST metastasis and matrix remodeling
Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew P. Voigt, Alexandra L. Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher S. Stipp, Rebecca D. Dodd
Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew P. Voigt, Alexandra L. Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher S. Stipp, Rebecca D. Dodd
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Research Article Oncology

PRC2 loss drives MPNST metastasis and matrix remodeling

Abstract

The histone methyltransferase PRC2 plays a complex role in cancer. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with frequent loss-of-function mutations in PRC2 that are associated with poor outcome. Here, we identify a critical role for PRC2 loss in driving MPNST metastasis. PRC2-dependent metastatic phenotypes included increased collagen-dependent invasion, upregulation of matrix-remodeling enzymes, and elevated lung metastasis in orthotopic mouse models. Furthermore, clinical sample analysis determined that PRC2 loss correlated with metastatic disease, increased fibrosis, and decreased survival in patients with MPNSTs. These results may have broad implications for PRC2 function across multiple cancers and provide a strong rationale for investigating potential therapies targeting ECM-remodeling enzymes and tumor fibrosis to improve outcomes in patients with MPNSTs.

Authors

Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew P. Voigt, Alexandra L. Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher S. Stipp, Rebecca D. Dodd

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Figure 7

PRC2 loss correlates with increased metastasis, fibrosis, and ECM gene expression in patient MPNST.

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PRC2 loss correlates with increased metastasis, fibrosis, and ECM gene e...
(A) Expression of LOX, LOXL1, COL1A1, and COL1A2 mRNA is increased in PRC2 mutant (ΔPRC2) compared with PRC2 wild-type (WT) patient samples. Previously published data set with Fisher’s exact t test (19). (B–G) Analysis of a tissue microarray and correlative clinical data. (B) IHC staining for H3K27me3 identifies PRC2-high and PRC2-low MPNSTs (red box) in tumor cores. (C) Representative images of MPNSTs with high (left) and low H3K27me3 (right). (D) Metastatic disease correlates with lower H3K27me3 in MPNST patients by Fisher’s exact t test. (E) Overall survival is decreased in patients with lower H3K27me3 scores. Classification of H3K27me3-low and -high indicated by red box in B (n = 14). (F) Histological analysis of Masson’s trichrome staining in MPNST tumor cores shows a broad range of tumor fibrosis. (G and H) PRC2 loss correlates with high trichrome staining and increased tumor fibrosis. Principal component analysis (PCA) and χ2 analysis of H3K27me3 and Masson’s trichrome percentage cell-positive staining with low and high classifiers assigned as indicated by a red circle (H3K27me high) and black circle (H3K27me3 low). Data represent biological replicates with the mean ± SD; *P < 0.05, **P < 0.01, ****P < 0.0001. CPM, counts per million.