# PDGF D and Prostate Cancer Bone Metastasis

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $353,695

## Abstract

   
DESCRIPTION (provided by applicant):  Prostate cancer (PCa) bone metastases are generally categorized as osteoblastic, based on radiographic imaging. However, on a cellular level, most patients have components of both bone resorption (osteoclastogenesis) and bone formation (osteoblastogenesis). Recently, we uncovered a PDGF D-initiated, novel protease/growth factor signaling network, critical for intraosseous PCa growth. Secreted as a latent homodimer, PDGF D contains a N-terminal CUB domain and a C-terminal growth factor domain (GFD). The proteolytic removal of the CUB domain is required for the growth factor domain dimer (PDGF D GFD-D) to activate its cognate receptor, β-PDGFR. We demonstrated that the serine protease matriptase processes latent PDGF D into its active form in a 2-step manner. This involves the generation of a hemidimer (PDGF D HD), an intermediate form consisting of one full-length PDGF D chain and a single GFD subunit. Our preliminary studies have led us to hypothesize that PCa-derived PDGF D is capable of preparing a metastatic niche within the bone by inducing osteoclast activation via PDGF D HD-specific signaling (Aim 1), and by promoting human mesenchymal stem cell (hMSC) differentiation into osteoblasts through both PDGF D HD and GFD-D signaling (Aim 2). With regard to osteoblastogenesis, we further postulate that PDGF D HD activates the TGFR/BMPR/SMAD signaling cascade, while PDGF D GFD-D preferentially activates the classic β-PDGFR/Akt/p38 signaling in hMSCs. We further hypothesize that PDGF D-initiated bone remodeling is critical for intraosseous PCa growth, and thus PDGF D and its proteolytic activator matriptase are potential therapeutic targets (Aim 3). Completion of the proposed study will uncover novel functions of PDGF D in bone remodeling critical for PCa bone metastasis and provide valuable information for the development of PDGF inhibitors based on PDGF ligand-specific biology.

## Key facts

- **NIH application ID:** 9839487
- **Project number:** 5R01CA123362-09
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Hyeong-Reh Choi Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,695
- **Award type:** 5
- **Project period:** 2010-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839487

## Citation

> US National Institutes of Health, RePORTER application 9839487, PDGF D and Prostate Cancer Bone Metastasis (5R01CA123362-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9839487. Licensed CC0.

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