# Lung Resident Mesenchymal Cells in the Pre-Metastatic Niche Formation

> **NIH NIH R01** · JACKSON LABORATORY · 2021 · $484,308

## Abstract

PROJECT SUMMARY/ABSTRACT
Metastatic disease remains the major cause of cancer-related death. Among the vital organs to which solid
tumors metastasize, the lung is one of the most common. Lung metastases frequently occur in various late
stage solid cancers including breast cancer. In the past 20 years, significant advances in lung metastasis
research have revealed intricate interactions between the disseminated tumor cells (DTCs) and the lung
microenvironment that are essential for the development of metastatic lung lesions. In particular, formation of
the immunosuppressive lung pre-metastatic microenvironment (niche), which is driven by factors secreted by
primary tumors, is regarded as a key preparation stage prior to the arrival of DTCs. The focus of this proposal
will be on the lung resident mesenchymal cells (MCs), an under-characterized stromal cell population within
the lung pre-metastatic niche. Preliminary studies in mouse models of breast cancer suggest that lung resident
MCs serve as a driver of immunosuppressive pre-metastatic niche formation by reprogramming diverse types
of myeloid cells to become highly immunosuppressive or tolerogenic. The central hypothesis of this proposal is
that lung resident MCs drive formation of the lung pre-metastatic niche by endowing diverse infiltrating
myeloid cells with an immunosuppressive capacity. To test this hypothesis and uncover mechanisms by
which MCs modulate myeloid cells, we propose three Specific Aims. Aim 1: Determine the lung resident MC
changes in the pre-metastatic niche using genetic manipulation of endogenous MCs in mice. We will
use orthotopic breast tumor cell implantation and genetically engineered mouse (GEM) tumor models to
measure the endogenous MC changes at the pre-metastatic stage. MCs will also be ablated in vivo to
determine their necessity for pre-metastatic niche formation. Aim 2: Characterize the key lung
mesenchymal factors that recruit and modulate myeloid cells. We will use RNA sequencing to profile
transcriptome changes between endogenous MCs residing in pre-metastatic vs. normal lungs to identify
upregulated genes that might play a role in modulating myeloid cells. The contribution of candidate MC genes
to pre-metastatic niche formation will be evaluated through MC-specific gene knockout. Aim 3: Target lung
MCs as a strategy for abolishing the immunosuppressive lung pre-metastatic niche in preclinical
models. Using orthotopic tumor implantation models, we will test the ability of lung MC blockade agents to
boost lung anti-tumor immunity and prevent lung metastasis. These studies will be a significant step toward our
long-term goal to fully dissect the roles of organ-specific stromal cells in organ-tropic metastases of breast
cancer. We anticipate that our findings will establish a strong foundation for the development of novel
therapeutic strategies that target stromal factors for the prevention and treatment of lung metastases of breast
cancer and other solid tumor...

## Key facts

- **NIH application ID:** 10209872
- **Project number:** 1R01CA251433-01A1
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Guangwen Ren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,308
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209872

## Citation

> US National Institutes of Health, RePORTER application 10209872, Lung Resident Mesenchymal Cells in the Pre-Metastatic Niche Formation (1R01CA251433-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10209872. Licensed CC0.

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