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

骨是前列腺癌转移最常见的靶部位，而不是软组织 绝佳的价钱这种选择性的原因尚不清楚，但骨微环境，包括 已显示成骨细胞和破骨细胞活性促进PCa生长。骨细胞 通过机械力转导对压力作出反应的OCys是在哺乳动物中最常见的细胞。 骨（>90%的骨细胞）。然而，OCys在PCa骨转移进展中的作用 还没有被阐明。我们现在已经确定PCa细胞，通过可溶性因子， 使OCys产生生长分化因子15（GDF 15），其刺激PCa细胞 入侵和生长。我们进一步鉴定了PCa细胞表达新的GDF-15受体， GDFN家族受体α样前体（GFRAL），尚未在癌症中探索 因此，它如何促进转移是一个知识空白。 除了直接靶向PCa细胞外，GDF 15还显示靶向PCa细胞。 微环境和诱导破骨细胞（OCl）的生产和随后的骨吸收 它可以促进PCa在骨骼中的播种和生长，我们发现破骨细胞 表达GFRAL。 此外，我们以前确定，骨微环境赋予了一个 对骨的化学耐药表型，并有初步数据表明， GDF 15：GFRAL有助于表型。综合起来，这些发现使我们 假设PCa训练OCys通过促进PCa骨转移， GDF 15：GFRAL轴。我们将通过以下目标来探讨这一假设： 目标1。确定GFRAL信号传导对PCa骨中细胞功能的作用 转移 目标2.确定OCys是否通过GDF 15：GFRAL轴促进骨转移 破骨细胞的活化。 目标3：确定GFRAL促进骨中化学抗性的机制。 我们相信，这些研究将为OCys和GFRAL在 前列腺癌骨转移和确定新的治疗靶点。

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.