Abstract Introduction. During metastasis, tumor cells interact extensively with cells in distant organs. These interactions can interfere or modify the function of the normal cells at metastatic sites to induce a more pro-tumor microenvironment. The lung is one of the most common sites of breast cancer (BC) metastasis, and alveolar epithelial cells are the most common cell type in the lung. My data suggests that the lung alveolar epithelium contributes to metastatic outgrowth, and I hypothesize that BC lung micrometastases activate surrounding lung epithelial cells which, in turn, support the outgrowth of BC metastases within the lung. The overall purpose of these studies is to identify factors secreted by resident lung epithelial cells that could be used as metastasis-specific therapeutic targets and/or agents. Methods. To test this hypothesis, I utilized immunocompetent preclinical metastatic mouse mammary carcinoma models to study lung metastatic outgrowth, the stage most relevant to patients diagnosed with metastatic disease. To quantify lung wound repair, I developed a custom multispectral imaging panel. Single-cell RNA-sequencing (scRNAseq) was performed on mouse lungs with high or low metastatic burden to identify genes in the lung epithelium that produce potentially targetable pro-metastatic factors. No-contact co-culture experiments were used to study reciprocal paracrine interactions between lung type II alveolar epithelial (AT2) and BC cells. Results. A wound repair-related phenotype, characterized by chronic inflammation, developed within the lung microenvironment during metastatic outgrowth, including an increase in the number and activation of AT2 cells surrounding metastases as they grow. Single-cell RNA-sequencing of mouse lungs with a high vs. low metastatic burden showed that metastatic outgrowth significantly changed AT2 gene expression resulting in a modified secretome. No-contact co-culture experiments indicated that TNBC cells directly alter AT2 gene expression, and AT2 secreted factors promoted TNBC growth. I investigated the possible mechanism(s) responsible for these effects and discovered that AT2 pulmonary surfactant protein and lipid levels are altered by BC-derived secreted factors. Interestingly, treatment with the naturally derived calf surfactant Infasurf, which contains native surfactant proteins/lipids and is FDA-approved for use in premature infants, inhibited BC cell proliferation. Conclusion. Low levels of surfactant are commonly associated with pulmonary disease and lung cancer. My BC lung metastasis data suggests that something similar may be occurring in the lungs during metastatic outgrowth. Overall, my studies demonstrate that in addition to directly targeting malignant cells, there is potential to target lung epithelial cells in the metastatic BC microenvironment as well, in order to effectively treat BC lung metastasis. Citation Format: J. L. Christenson, N. S. Spoelstra, K. I. O'Neill, M. M. Williams, J. K. Richer. Reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-03-28.
Christenson et al. (Tue,) studied this question.