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.

Public Health Relevance

Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer- related death most often due to bone metastasis. This project will explore how the cancer changes the bone environment so that it becomes conducive to bone metastasis. This will help identify targets to prevent or treat bone metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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University of Michigan Ann Arbor
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