Lung Resident Mesenchymal Cells in the Pre-Metastatic Niche Formation

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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 tumors.