Project 3: The osteocyte-driven GDF15:GFRAL axis promotes prostate cancer bone metastasis

骨是前列腺癌最常转移的部位，而不是软组织 地点。这种选择性的原因尚不清楚，但骨骼微环境，包括 成骨细胞和破骨细胞的活性，已被证明可以促进前列腺癌的生长。骨细胞 (OCys)通过机械转导对压力做出反应，是体内最常见的细胞 骨(90%的骨细胞)。然而，OCys在前列腺癌骨转移中的作用 还没有得到澄清。我们现在已经通过可溶性因子鉴定出前列腺癌细胞， 培养OCys产生生长分化因子15(GDF15)，刺激PCA细胞 入侵和发展。我们进一步证实，前列腺癌细胞表达新的GDF-15受体， GDFN家族受体α样前体(GFRNAL)在癌症中的作用尚未被发现 因此，它如何促进转移是一个知识的缺口。 除了直接靶向PCa细胞外，GDF15还被证明靶向 微环境和诱导破骨细胞(OCL)的产生及随之而来的骨吸收 可以促进PCA在骨中的种植和生长，我们鉴定了破骨细胞 快递GFRAL。 此外，我们以前发现，骨骼微环境赋予了 对骨的化疗耐药表型，初步数据表明 GDF15：GFra对表型有贡献。综上所述，这些发现引导我们 假设受过前列腺癌教育的OCys通过 GDF15：神经纤维轴。我们将通过以下目标探讨这一假设： 目的1.确定GFral信号在PCa骨细胞功能中的作用 转移。 目的2.确定OCys是否通过GDF15：GFra轴促进骨转移 破骨细胞的激活。 目的3.确定GFra促进骨化疗耐药的机制。 我们相信，这些研究将提供一个新的理解OCys和GFra在 Pca骨转移和寻找新的治疗靶点。

Bone is the most frequently targeted site for PCa metastasis as opposed to soft tissues site. The reason for this selectivity is unknown but the bone microenvironment, including osteoblast and osteoclast activity, have been show to promote PCa growth. Osteocytes (OCys), which respond to pressure through mechanotransduction, are the most common cell in bone (>90% of bone cells). However, the role of OCys in progression of PCa bone metastasis has not been elucidated. We have now identified that PCa cells, through soluble factors, educate OCys to produce Growth differentiation factor 15 (GDF15), which stimulates PCa cell invasion and growth. We further identified that PCa cells express the novel GDF-15 receptor, GDFN family receptor alpha-like precursor (GFRAL), which has not been explored in cancer and thus, how it contributes to metastasis is a gap of knowledge. In addition to directly targeting the PCa cells, GDF15 has been shown to target the microenvironment and induce osteoclast (OCl) production and subsequent bone resorption which can promote seeding and growth of PCa in bone and we identified that osteoclasts express GFRAL. Furthermore, we previously identified that the bone microenvironment confers a chemoresistant phenotype to bone and have preliminary data suggesting that the GDF15:GFRAL contributes to the phenotype. Taken together, these findings lead us to hypothesize that PCa-educated OCys promote PCa bone metastasis through the GDF15:GFRAL axis. We will explore this hypothesis through the following aims: Aim 1. Determine the role of GFRAL signaling on cellular function in PCa bone metastasis. Aim 2. Determine if OCys promote bone metastasis through GDF15:GFRAL axis activation of osteoclasts. Aim 3. Identify mechanisms through which GFRAL promotes chemoresistance in bone. We believe these studies will provide a new understanding of the role of OCys and GFRAL in PCa bone metastasis and identify novel therapeutic targets.