# Effect of skeletal compression on tumor growth and migration

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $78,750

## Abstract

PROJECT SUMMARY
The long-term objective of this NCI R03 project (Effect of skeletal compression on tumor growth and
migration) is to contribute to developing guidelines for physical therapies that most effectively reduce the risk of
cancer induction and relapse. The specific goal of this project is to evaluate the role of skeletal compression
(bone loading) in regulating tumor growth and epithelial-to-mesenchymal transition (EMT) in the bone
microenvironment. Focusing on bone metastasis associated with breast cancer, we will evaluate interactions of
tumor cells with osteocytes, the most abundant type of cells in bone matrix, in the presence and absence of
mechanical stimulation. One out of eight women suffers breast cancer in her lifetime, and bone is one of the
most frequent sites of metastasis. Currently, we know little about the impact of osteocyte-driven
mechanotransduction in tumor-bone interactions and bone metastasis. Preliminary studies suggest that
osteocytes act as an attractant of tumor cells, but application of fluid flow shear stress reverses the attraction
and leads to EMT. An intriguing question is whether mechanical stimulation to osteocytes may act as a
regulatory switch of tumor EMT. Our working hypothesis is: Mechanical stimulation inhibits proliferation and
stimulates migration of tumor cells in the loaded bone by regulating Src in tumor-osteocyte interactions. To test
this hypothesis, we will conduct two specific aims:
Aim 1: Evaluate the effect of skeletal compression in tumor growth and invasion using a mouse model.
Aim 2: Determine the mechanism of action of mechanical stimulation in tumor-osteocyte interactions.
In Aim 1, we will use a mouse model of skeletal loading to determine tumor growth and migration associated
with breast cancer (mammary tumor) in the bone microenvironment. In Aim 2, we will employ monolayer cell
cultures and 3D spheroids to evaluate tumor-osteocyte interactions in the presence and absence of oscillatory
fluid flow shear stress. We will focus on genes involved in EMT and mechanotransduction of bone such as TGFβ
and Src, as well as mechano-sensitive factors (e.g., fibronectin, heat shock protein, nucleolin) that were identified
by mass spectrometry in osteocyte-derived conditioned mediums. We expect that this project will contribute to
a basic understanding of the role of skeletal compression in tumor growth and invasion in the bone
microenvironment. We also expect that the results will contribute to the provision of risk-benefit analysis of
loading-linked physical activities, such as walking and jogging, as well as the establishment of a therapeutic
guideline for bone metastasis.

## Key facts

- **NIH application ID:** 9889087
- **Project number:** 5R03CA238555-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Hiroki Yokota
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,750
- **Award type:** 5
- **Project period:** 2019-03-07 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889087

## Citation

> US National Institutes of Health, RePORTER application 9889087, Effect of skeletal compression on tumor growth and migration (5R03CA238555-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9889087. Licensed CC0.

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