# Role of Perivascular Mesenchymal Stem Cells (pMSCs) in the Bone Marrow Niche and the Extracellular Matrix in the Control of Skeletal Metastasis

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $368,288

## Abstract

TECHNICAL ABSTRACT
The skeleton is a preferred organ for cancer dissemination from various tumors malignancies. The main
objective of this research proposal is to understand the function of the Bone Marrow microenvironment, and
specifically of its perivascular components, in the establishment of skeletal metastasis.
The studies that are proposed aim to test the innovative hypothesis that Mesenchymal Stem Cells (MSCs),
as perivascular cells (pMSCs), function as gatekeepers controlling tumor cell invasion to the bone. This
new hypothesis provides clinically relevant information for therapeutic strategies that innovately aim at
reducing the engraftment of circulating cancer cells by closing the gate through which the metastatic cell transit
into the normal bone. We propose that the inhibition of one or combination of tumor cells and pMSCs
specific genes would prevent or attenuate the metastatic process in vivo.
To experimentally dissect the various cellular and extracellular matrix components controlling extravasation,
we have designed and validated a unique in vivo extraskeletal humanized bone marrow niche-mimicking
platform (humanized Ossicle). This platform is centered around the use of a porous, calcium phosphate
ceramic into which human bone marrow-derived MSCs (hBM-MSC) are loaded and then implanted into the
back of immune deficient mice. Bone is fabricated onto the walls of the ceramic by hBM-MSCs anchored at
these locations and, at the centers; the host-derived blood vessels have pMSCs within the marrow space.
We have documented that when melanoma is injected into the blood stream of the mouse, the bones become
black (melanin), as is the bone in habitat. If we manipulate the expression of molecules are we propose
involved in the process, such as CXCL12 or MCAM in the pMSCs, the mouse bone is black and the habitat is
white. This black-and-white result sets the stage for Specific Aim 1 where we dissect the participation of
pMSCs and the perivascular basement membrane in driving Skeletal Metastasis. In Specific Aim 2, we
propose to determine the participation of HSC-niche ligand molecules expressed on cancer cells in
driving SM.
We have established a baseline using melanoma, which has the highest rate of lethality once it metastasizes
into bone. This proposal will also be focused on the study of molecular mechanisms using breast cancer cell
lines. A logical extension of this platform is to provide a predictive diagnostic for the patients' control over
metastasis for different osteotropic cancers.
In addition to the significant direct clinical impact, this proposed work is expected also to provide the platform
for future projects addressing the roles of pMSCs that may influence other skeletal metastasis, such as
regulation of local antitumor immune response, cancer cells dormancy and tumor angiogenesis, and to serve
as template for the study of other osteotropic malignancies (prostate and lung cancer), thus broadening the
significance of the fin...

## Key facts

- **NIH application ID:** 10028072
- **Project number:** 1R01CA251612-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Arnold Irwin Caplan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,288
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10028072

## Citation

> US National Institutes of Health, RePORTER application 10028072, Role of Perivascular Mesenchymal Stem Cells (pMSCs) in the Bone Marrow Niche and the Extracellular Matrix in the Control of Skeletal Metastasis (1R01CA251612-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10028072. Licensed CC0.

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