Asporin restricts mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression

Robert M. Hughes, Brian W. Simons, Hamda Khan, Rebecca Miller, Valentina Kugler, Samantha Torquato, Debebe Theodros, Michael C. Haffner, Tamara Lotan, Jessie Huang, Elai Davicioni, Steven S. An, Ryan C. Riddle, Daniel L.J. Thorek, Isla P. Garraway, Elana J. Fertig, John T. Isaacs, W. Nathaniel Brennen, Ben H. Park, Paula J. Hurley

Research output: Contribution to journalArticle

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 CD8þ 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.

Original languageEnglish (US)
Pages (from-to)3636-3650
Number of pages15
JournalCancer Research
Volume79
Issue number14
DOIs
StatePublished - Jan 1 2019

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Tumor Microenvironment
Mesenchymal Stromal Cells
Cell Differentiation
Neoplasms
Neoplasm Metastasis
Neoplastic Stem Cells
Allografts
Prostate
T-Lymphocytes
Lung

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Asporin restricts mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression. / 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.; Nathaniel Brennen, W.; Park, Ben H.; Hurley, Paula J.

In: Cancer Research, Vol. 79, No. 14, 01.01.2019, p. 3636-3650.

Research output: Contribution to journalArticle

Hughes, RM, Simons, BW, Khan, H, Miller, R, Kugler, V, Torquato, S, Theodros, D, Haffner, MC, Lotan, T, Huang, J, Davicioni, E, An, SS, Riddle, RC, Thorek, DLJ, Garraway, IP, Fertig, EJ, Isaacs, JT, Nathaniel Brennen, W, Park, BH & Hurley, PJ 2019, 'Asporin restricts mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression', Cancer Research, vol. 79, no. 14, pp. 3636-3650. https://doi.org/10.1158/0008-5472.CAN-18-2931
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. ; Nathaniel Brennen, W. ; Park, Ben H. ; Hurley, Paula J. / Asporin restricts mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression. In: Cancer Research. 2019 ; Vol. 79, No. 14. pp. 3636-3650.
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