Multiple pathways coordinating reprogramming of endothelial cells into osteoblasts by BMP4

• Published in: iScience Vol. 24; no. 4; p. 102388
• Main Authors: Yu, Guoyu, Shen, Pengfei, Lee, Yu-Chen, Pan, Jing, Song, Jian H., Pan, Tianhong, Lin, Song-Chang, Liang, Xin, Wang, Guocan, Panaretakis, Theocharis, Logothetis, Christopher J., Gallick, Gary E., Yu-Lee, Li-Yuan, Lin, Sue-Hwa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-04-2021; Elsevier
• Subjects: Cancer; Cell Biology; Molecular Biology; Molecular Biology; Cell Biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102388

Cell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial cell-to-osteoblast (EC-to-OSB) transition. Such tumor-induced stromal reprogramming supports prostate cancer progression. We delineate signaling pathways mediating EC-to-OSB transition using EC lines 2H11 and SVR. We found that BMP4-activated pSmad1-Notch-Hey1 pathway inhibits EC migration and tube formation. BMP4-activated GSK3β-βcatenin-Slug pathway stimulates Osx expression. In addition, pSmad1-regulated Dlx2 converges with the Smad1 and β-catenin pathways to stimulate osteocalcin expression. By co-expressing Osx, Dlx2, Slug and Hey1, we were able to achieve EC-to-OSB transition, leading to bone matrix mineralization in the absence of BMP4. In human prostate cancer bone metastasis specimens and MDA-PCa-118b and C4-2b-BMP4 osteogenic xenografts, immunohistochemical analysis showed that β-catenin and pSmad1 are detected in activated osteoblasts rimming the tumor-induced bone. Our results elucidated the pathways and key molecules coordinating prostate cancer-induced stromal programming and provide potential targets for therapeutic intervention.
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•BMP4 upregulates several pathways essential for EC-to-OSB transition•BMP4 activates pSmad1-Notch-Hey1 and GSK3β-βcatenin-Slug-OSX pathways•pSmad1-regulated Dlx2 expression connects the pSmad1 and β-catenin pathways•Coexpression of OSX, Dlx2, Slug, and Hey1 is sufficient to induce EC-to-OSB transition
Molecular Biology ; Cell Biology ; Cancer