Supplementary Data from 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.; Brennen, W. Nathaniel; Park, Ben H.; Hurley, Paula J.

doi:10.1158/0008-5472.22421327.v1

00085472can182931-sup-208940_2_supp_5512925_pr94cc.pdf (1.12 MB)

Supplementary Data from Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression

journal contribution

posted on 2023-03-31, 02:25 authored by 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

Figure S1: Comparison of Aspn+/+ and Aspn-/- mice. Figure S2: Representative gating of murine MSCs. Figure S3: ASPN restricts MSC differentiation. Figure S4: ASPN expression in cancer cell lines. Figure S5: ASPN increases cancer cell migration. Figure S6: ASPN expression in B6CaP allografts and organoids.

Funding

Department of Defense

NIH

Patrick C. Walsh Prostate Cancer Fund

Willowcroft Foundation

American Cancer Society

National Cancer Institute/NIH

History

ARTICLE 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. 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.