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Betaglycan drives the mesenchymal stromal cell osteogenic program and prostate cancer-induced osteogenesis

Oncogene volume 38, pages 6959–6969 (2019)Cite this article

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Abstract

Bone metastatic prostate cancer provokes extensive osteogenesis by driving the recruitment and osteoblastic differentiation of mesenchymal stromal cells (MSCs). The resulting lesions greatly contribute to patient morbidity and mortality, underscoring the need for defining how prostate metastases subvert the MSC–osteoblast differentiation program. To gain insights into this process we profiled the effects of co-culture of primary MSCs with validated bone metastatic prostate cancer cell line models. These analyses revealed a cast of shared differentially induced genes in MSC, including betaglycan, a co-receptor for TGFβ. Betaglycan has not been studied in the context of bone metastatic disease previously. Here we report that loss of betaglycan in MSC is sufficient to augment TGFβ signaling, proliferation and migration, and completely blocks the MSC–osteoblast differentiation program. Further, betaglycan was revealed as necessary for prostate cancer-induced osteogenesis in vivo. Mechanistically, gene expression analysis revealed betaglycan controls the expression of a large repertoire of genes in MSCs, and that betaglycan loss provokes >60-fold increase in the expression of Wnt5a that plays important roles in stemness. In accord with the increased Wnt5a levels, there was a marked induction of canonical Wnt signaling in betaglycan ablated MSCs, and the addition of recombinant Wnt5a to MSCs was sufficient to impair osteogenic differentiation. Finally, the addition of Wnt5a neutralizing antibody was sufficient to induce the expression of osteogenic genes in betaglycan-ablated MSCs. Collectively, these findings suggest a betaglycan–Wnt5a circuit represents an attractive vulnerability to ameliorate prostate cancer-induced osteogenesis.

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Acknowledgements

We thank Dr. Colm Morrissey, University of Washington for providing human bone metastatic prostate cancer specimens (P50-CA097186 16A1). LMC was supported by a fellowship from the American Cancer Society (PF-13-175-01-CSM). This work has been supported in part by the Molecular Genomics Core, the Analytic Microscopy Core, the Small Animal Imaging Laboratory Core and the Biostatistics and Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). Funding also provided by Miles for Moffitt (CCL), the Department of Defense PCRP program (W81XWH1810523; CCL), and by the Cortner-Couch Endowed Chair for Cancer Research from the University of South Florida (JLC).

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Authors and Affiliations

  1. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Leah M. Cook

  2. Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Jeremy S. Frieling, Niveditha Nerlakanti, Jeremy J. McGuire, Karen L. Burger, John L. Cleveland & Conor C. Lynch

  3. Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA

    Niveditha Nerlakanti & Jeremy J. McGuire

  4. Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Paul A. Stewart

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LMC, CCL, JSF, and KLB designed research; LMC, JSF, NN, and JJM performed research; LMC, KLB, PS, JSF, JLC, and CCL contributed new reagents/analysis tools and also analyzed the data; LMC, JSF, JLC, and CCL wrote the paper.

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Cook, L.M., Frieling, J.S., Nerlakanti, N. et al. Betaglycan drives the mesenchymal stromal cell osteogenic program and prostate cancer-induced osteogenesis. Oncogene 38, 6959–6969 (2019). https://doi.org/10.1038/s41388-019-0913-4

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