Abstract A001: Reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth
Authors: Christenson Jessica L. , Spoelstra Nicole S. , Richer Jennifer K. 
Published: November 2024

Introduction. During metastasis, tumor cells interact extensively with endogenous cells in distant organs. These interactions change the behavior of these surrounding cell populations, often inducing a more pro-tumor microenvironment. The lung is one of the most common sites of breast cancer (BC) metastasis, and in the lung, alveolar epithelial cells are the most common cell type. My data suggest 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 BC metastasis models to study lung metastatic outgrowth, the stage at which most patients are diagnosed with metastatic disease. A custom imaging panel was developed to quantify lung wound repair, and 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 secreted factors. No-contact co-culture experiments were used to directly 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, while 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 proliferation. Conclusion. Low levels of surfactant are commonly associated with pulmonary disease and lung cancer. My BC lung metastasis data suggest that something similar may be occurring in the lungs during metastatic outgrowth. Overall, my studies demonstrate the potential for targeting lung epithelial cells in the metastatic microenvironment, in addition to directly targeting malignant cells, as an effective way to treat and manage BC lung metastases.

Citation Format: Jessica L. Christenson, Nicole S. Spoelstra, Jennifer K. Richer. Reciprocal activation of breast cancer metastases and the lung epithelium during metastatic outgrowth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A001.