@article{f424b5ae4b9942f9b2071b61bf34dccb,
title = "Asporin restricts mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression",
abstract = "Tumor progression to metastasis is not cancer cell autonomous, but rather involves the interplay of multiple cell types within the tumor microenvironment. Here we identify asporin (ASPN) as a novel, secreted mesenchymal stromal cell (MSC) factor in the tumor microenvironment that regulates metastatic development. MSCs expressed high levels of ASPN, which decreased following lineage differentiation. ASPN loss impaired MSC self-renewal and promoted terminal cell differentiation. Mechanistically, secreted ASPN bound to BMP-4 and restricted BMP-4–induced MSC differentiation prior to lineage commitment. ASPN expression was distinctly conserved between MSC and cancer-associated fibroblasts (CAF). ASPN expression in the tumor microenvironment broadly impacted multiple cell types. Prostate tumor allografts in ASPN-null mice had a reduced number of tumor-associated MSCs, fewer cancer stem cells, decreased tumor vasculature, and an increased percentage of infiltrating CD8{\th} T cells. ASPN-null mice also demonstrated a significant reduction in lung metastases compared with wild-type mice. These data establish a role for ASPN as a critical MSC factor that extensively affects the tumor microenvironment and induces metastatic progression.",
author = "Hughes, {Robert M.} and Simons, {Brian W.} and Hamda Khan and Rebecca Miller and Valentina Kugler and Samantha Torquato and Debebe Theodros and Haffner, {Michael C.} and Tamara Lotan and Jessie Huang and Elai Davicioni and An, {Steven S.} and Riddle, {Ryan C.} and Thorek, {Daniel L.J.} and Garraway, {Isla P.} and Fertig, {Elana J.} and Isaacs, {John T.} and {Nathaniel Brennen}, W. and Park, {Ben H.} and Hurley, {Paula J.}",
note = "Funding Information: T.L. Lotan reports receiving other commercial research support from GenomeDx, Ventana/Roche, Myriad Genomics, and is a consultant/advisory board member for Janssen. E. Davicioni has ownership interest (including stock, patents, etc.) in GenomeDx. D.L.J. Thorek has ownership interest (including stock, patents, etc.) in Diaprost AB and is a consultant/advisory board member for Diaprost AB. B.H. Park reports receiving a commercial research grant from Abbvie, reports receiving other commercial research support from Foundation Medicine, has ownership interest (including stock, patents, etc.) in Loxo Oncology, and is a consultant/advisory board member for Loxo Oncology. No potential conflicts of interest were disclosed by the other authors. Funding Information: We thank Edward M. Schaeffer, Ashley E. Ross, Daniel Ardeljan, Leigh Ellis, Daniele M. Gilkes, In{\^e}s Godet, Timothy E. Krueger, and Karen Cravero for thoughtful discussions and for sharing resources and experimental protocols. We thank the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Flow Cytometry and Cell Imaging Core Facilities supported by the Cancer Center Core Grant P30 CA006973. We also thank the Prostate Cancer Biorepository Network (PCBN), supported by the Department of Defense Prostate Cancer Research Program, Department of Defense Award No. W81XWH-10-2-0056 and W81XWH-10-2-0046. We acknowledge the use of tissues procured by the National Disease Research Interchange (NDRI) Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
doi = "10.1158/0008-5472.CAN-18-2931",
language = "English (US)",
volume = "79",
pages = "3636--3650",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "14",
}