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 2

PRC2 deletion alters interaction with collagen matrix.

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PRC2 deletion alters interaction with collagen matrix. (A) Representativ...
(A) Representative images (original magnification, 20×) of NP1, NP2, and NC1 cell panels showing clustering phenotype observed after Transwell invasion (n = 4). (B) Quantification of cell clusters from Transwell invasion assays showing increased number of clusters with PRC2 loss. Total number of clusters was analyzed by Kruskal-Wallis with multiple comparisons. (Area = 0.546 mm2) (n = 4). (C) Phase-contrast movies of NC1 cells plated on collagen for 18 hours before capturing cell dynamics via 5-minute increment frames for 20 hours (1,200 minutes; original magnification, 10×). Yellow and pink arrows denote key cell motility features of the same cell across multiple frames. Little movement is seen in the NT cells, while the formation of cell clusters (ΔEed frames) and rapid movement (ΔSuz12 frames) are observed with PRC2 loss (n = 3). (D) Representative images of movies (original magnification, 10×) with cell motility tracks highlighted. (E) Cell motility tracks (n = 25) plotted on an x/y coordinate graph illustrate total displacement by color ring of NT (left), ΔEed (middle), and ΔSuz12 (right). Quantification of total displacement over time is calculated with total displacement (μM) using area under the curve analysis. Scale bars at 200 μm. Data represent individual clusters with the mean ± SD; *P < 0.05.