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

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $187,977

## Abstract

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.

## Key facts

- **NIH application ID:** 9935669
- **Project number:** 2P01CA093900-16
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Evan T Keller
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,977
- **Award type:** 2
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935669

## Citation

> US National Institutes of Health, RePORTER application 9935669, Project 3: The osteocyte-driven GDF15:GFRAL axis promotes prostate cancer bone metastasis (2P01CA093900-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9935669. Licensed CC0.

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