Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression.

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ID: 74501
2019
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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 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. SIGNIFICANCE: These findings show that asporin regulates key properties of mesenchymal stromal cells, including self-renewal and multipotency, and asporin expression by reactive stromal cells alters the tumor microenvironment and promotes metastatic progression.
Reference Key
hughes2019asporincancer Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Hughes, Robert M;Simons, Brian W;Khan, Hamda;Miller, Rebecca;Kugler, Valentina;Torquato, Samantha;Theodros, Debebe;Haffner, Michael C;Lotan, Tamara;Huang, Jessie;Davicioni, Elai;An, Steven S;Riddle, Ryan C;Thorek, Daniel L J;Garraway, Isla P;Fertig, Elana J;Isaacs, John T;Brennen, W Nathaniel;Park, Ben H;Hurley, Paula J;
Journal Cancer research
Year 2019
DOI
10.1158/0008-5472.CAN-18-2931
URL
Keywords
transcriptome asporin/plap-1 follicle growth secondary follicle theca cell

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