PDGF D and Prostate Cancer Bone Metastasis

 描述（由申请人提供）：根据放射学成像，前列腺癌（PCa）骨转移通常归类为成骨细胞。然而，在细胞水平上，大多数患者具有骨吸收（破骨细胞生成）和骨形成（成骨细胞生成）的成分。最近，我们发现了PDGF D启动的新的蛋白酶/生长因子信号网络，对骨内PCa生长至关重要。作为潜在的同二聚体分泌，PDGF D含有N-末端CUB结构域和C-末端生长因子结构域（GFD）。CUB结构域的蛋白水解去除是生长因子结构域二聚体（PDGF D GFD-D）激活其同源受体β-PDGFR所必需的。我们证明丝氨酸蛋白酶间质蛋白酶以2步方式将潜在的PDGF D加工成其活性形式。这涉及半二聚体（PDGF D HD）的产生，半二聚体是由一个全长PDGF D链和单个GFD亚基组成的中间形式。我们的初步研究使我们假设，PCA衍生的PDGF D能够通过PDGF D HD特异性信号传导诱导破骨细胞活化（Aim 1），并通过PDGF D HD和GFD-D信号传导促进人间充质干细胞（hMSC）分化成成骨细胞（Aim 2），在骨内制备转移性小生境。关于成骨细胞生成，我们进一步假设PDGF D HD激活TGF β R/BMPR/SMAD信号级联，而PDGF D GFD-D优先激活hMSC中经典的β-PDGFR/Akt/p38信号。我们进一步假设PDGF D启动的骨重塑对于骨内PCa生长至关重要，因此PDGF D及其蛋白水解激活剂间质蛋白酶是潜在的治疗靶点（目的3）。该研究的完成将揭示PDGF D在骨重建中的新功能，这对PCa骨转移至关重要，并为基于PDGF配体特异性生物学的PDGF抑制剂的开发提供有价值的信息。

 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.