# Role of Bone in Primary and Metastatic Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $353,076

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Faccio, Roberta, PhD
ABSTRACT
 Recent evidence from our lab and others indicates that the insurgence of a primary tumor leads to changes
in the bone microenvironment that affect the residing hematopoietic and mesenchymal populations. These
changes in the bone microenvironment occur during the early stages of tumor development, prior to any evidence
of metastatic dissemination, and become more pronounced while the primary tumor progresses, even in tumors
that do not metastasize to the bone. We find increased numbers of immature myeloid cells that can actively
suppress T cell proliferation in bone marrow of mice bearing primary breast tumors and in newly diagnosed stage
II-III breast cancer patients compared with controls. In addition to changes in immune populations, bone residing
osteoblasts and osteocytes, normally involved in bone formation and regulation of bone homeostasis, respond
to distal tumors by upregulating various inflammatory cytokines as well as inhibitors of the Wnt signaling pathway,
such as Dkk1. Several of these bone-produced factors act locally to change the basal bone homeostasis, but
can also have systemic effects that can impact, either directly or indirectly, primary tumor growth and future
tumor dissemination to various sites.
Wnt signaling plays important roles in bone development, hematopoiesis and cancer. Dkk1 is a Wnt/β-catenin
inhibitor, known to suppress bone formation and promote bone resorption. Increased levels of Dkk1 are often
observed in cancer patients and correlate with poor prognosis. We recently reported that Dkk1 is upregulatated
by osteoblasts and osteocytes in the bone of mice with primary breast tumors and in cancer associated
fibroblasts (CAFs) in the primary site, but at a level much lower than in the bone. Intriguingly, we found that Dkk1
exerts immune suppressive effects and its neutralization decreases primary tumor growth by reducing immature
myeloid populations and enhancing T cell immune surveillance. Based on these exciting findings, our central
hypothesis is that bone residing osteoblasts and osteocytes modulate primary breast cancer growth and
metastatic dissemination to multiple sites by creating a systemic immune suppressive environment via
production of Dkk1. Aim1. Exploring the role of the bone microenvironment during tumor progression.
The goal of this aim is to determine the anti-tumor effects of Dkk1 deletion in bone versus its deletion at tumor
site. Aim2. Determine the mechanism by which Dkk1 modulates immune suppression. The goal of this
aim is to determine the cellular mechanism by which Dkk1 induces immune suppression.
OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page 1 Continuation Format Page

## Key facts

- **NIH application ID:** 10442364
- **Project number:** 5R01CA235096-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Roberta Faccio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $353,076
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442364

## Citation

> US National Institutes of Health, RePORTER application 10442364, Role of Bone in Primary and Metastatic Cancer (5R01CA235096-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10442364. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*