# Project 4: The role of bone marrow macrophages in skeletal metastasis

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $187,968

## Abstract

Abstract: When prostate cancer (PCa) cells localize in bone they encounter osteal macrophages in the
marrow/tumor microenvironment. The specific function of macrophages in apoptotic cancer cell clearance, a
process termed efferocytosis, leads to a pro-inflammatory immunosuppressive cascade that supports further
tumor growth. Findings from the project laboratory in the previous cycle support a strategy to allow apoptotic
cell engulfment to occur in a robust and resolving manner while reducing the adverse signaling and hence
reorienting the macrophage program that occurs when they engulf a cancer cell. It is critical to identify the
specific mediators responsible for the pro-inflammatory immunosuppressive response and selectively target
them while promoting efferocytosis and resolution. An efferocytic recognition signal, T cell immunoglobulin and
mucin-domain containing-3 (Tim-3) has been identified as a strong candidate in the recognition of
phosphatidylserine on an apoptotic cell and the downstream deleterious signaling operative in tumor
associated macrophages. The overall hypothesis is that macrophage efferocytosis of apoptotic prostate
cancer cells triggers immunosuppressive signaling which supports cancer growth in bone that can be
targeted as a novel cancer therapy. Three aims include; 1) To determine the role of efferocytosis-induced
Tim-3 in macrophages and its ability to accelerate tumor growth in bone, 2) To elucidate targetable
mechanisms of the signaling pathways triggered by efferocytosis of prostate cancer cells that support
immunosuppression and tumor growth in bone, and 3) To identify the specific gene-expression signature of
bone marrow efferocytic monocytes/macrophages during skeletal metastasis. Strategies for this project will
include meticulous targeting of the efferocytic receptor Tim-3 with selective antibodies and a gene targeted
mouse model, single cell RNA-seq analyses of the unique transcriptional profile of efferocytic tumor associated
macrophages, and dysregulation of the signaling pathway for Tim-3 with known and synthesized biochemical
targets. Interactions with the other PO1 projects will leverage osteocytic derived factors, abscisic acid, and the
polyploid status of cancer cells to identify their roles in the tumor microenvironment that macrophages
orchestrate to lead to catastrophic tumor growth. Efferocytic macrophages provide gatekeeping activities in the
tumor microenvironment that are particularly relevant in the skeletal metastatic lesion. Targeting the signaling
of efferocytic macrophages in the bone marrow provides a new avenue that will benefit the design of patient
therapeutics for the treatment of prostate cancer skeletal metastasis.

## Key facts

- **NIH application ID:** 9935670
- **Project number:** 2P01CA093900-16
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Laurie K. McCauley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,968
- **Award type:** 2
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935670

## Citation

> US National Institutes of Health, RePORTER application 9935670, Project 4: The role of bone marrow macrophages in skeletal metastasis (2P01CA093900-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9935670. Licensed CC0.

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