Metastasis-Associated Wound Repair Promotes Reciprocal Lung Epithelium Activation and Breast Cancer Metastatic Outgrowth

When tumor cells colonize distant organs during metastasis, they interact extensively with surrounding cells. These interactions often change the behavior of surrounding cell populations which collectively induce a protumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast Cancer metastasis. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth in immunocompetent preclinical mouse models of breast Cancer. This phenotype was characterized by an increased number and activation of lung type II alveolar epithelial (AT2) cells surrounding growing metastases. Metastatic outgrowth significantly changed AT2 gene expression, resulting in a modified secretome. AT2-derived secreted factors also promoted triple-negative breast Cancer growth. AT2-secreted factors are regulated by the cyclic adenosine monophosphate response element-binding protein (CREB). Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2 breast Cancer reciprocal interactions in vitro and metastatic outgrowth in vivo. Finally, AT2 cells adjacent to metastases in lungs from patients with metastatic breast Cancer expressed higher PDE4B compared with AT2 cells in normal lungs.

Significance: Alveolar epithelial cells are the most common cell type in the lung. Our studies demonstrate the potential for targeting metastasis-associated wound repair and lung epithelial cell activation during metastatic outgrowth with FDA-approved PDE4 inhibitors. This strategy may be an effective way to treat and manage progression of established metastatic breast Cancer within the lung.