Metastasis-associated wound repair promotes reciprocal activation of the lung epithelium and breast cancer metastases during 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 pro-tumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast cancer (BC) metastasis. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth in immunocompetent preclinical mouse models of BC. 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 promote TNBC growth. AT2 secreted factors are regulated by the cAMP response element-binding protein (CREB). Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo. STATEMENT OF 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 BC.