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

Leah M Cook, Jeremy S Frieling, Niveditha Nerlakanti, Jeremy J McGuire, Paul A Stewart, Karen L Burger, John L Cleveland, Conor C Lynch

Oncogene 2019 Oct

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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.

Citation

Leah M Cook, Jeremy S Frieling, Niveditha Nerlakanti, Jeremy J McGuire, Paul A Stewart, Karen L Burger, John L Cleveland, Conor C Lynch. Betaglycan drives the mesenchymal stromal cell osteogenic program and prostate cancer-induced osteogenesis. Oncogene. 2019 Oct;38(44):6959-6969