The Biology of Lung Metastasis in Breast Cancer

Metastasis is the major cause of mortality in human breast cancer. The mechanisms by which the primary tumor microenvironment promotes the invasion and intravasation of tumor cells has been extensively studied. In contrast, the mechanisms regulating extravasation of blood-borne tumor cells at distal sites, their survival and proliferation in their new microenvironment, and their re-dissemination to additional sites, are less studied and not well understood. Therefore, the investigation of the mechanisms that regulate breast cancer cells at the metastatic site are an area of intense scientific interest with important clinical applications. CTCs efficiently disseminate throughout the body but form metastases with low frequency. The CTCs that successfully extravasate, survive and grow at distal sites have acquired stem-like characteristics that promote these processes. The acquisition of stem-like properties is closely linked to the epithelial-mesenchymal transition (EMT). Thus, the transcriptional control of stemness and EMT is an important regulator of metastatic efficiency. Stemness and/or EMT is induced by metabolic, hypoxic and redox stress, as well as by interactions with macrophages and platelets. Understanding the regulation of tumor cell stemness by stromal cells could lead to the identification of novel therapeutic targets for the treatment of metastatic disease. Previous studies on the role of stemness in metastasis to distal sites has been significantly limited by the analytic methods used. We have developed ground-breaking new techniques that allow us to directly interrogate the relationship between stemness and the efficiency of extravasation, survival and growth in vivo. Our novel imaging methods combine the use of a permanent lung imaging window compatible with multiphoton microscopy, novel computational reconstructions of large fields of view, and newly developed biosensors that report on the induction of stemness, hypoxia and ROS. These tools allow the visualization and analysis of breast cancer cells as they extravasate and form metastatic colonies in the lung. In contrast, traditional end-point analyses of fixed tissues cannot provide information on the role of stemness during extravasation and metastatic growth. This Program Project is organized around three major questions. First, we will define the signaling pathways that regulate breast cancer cells in the lung metastatic niche. Second, we will explore the induction of stem-like properties in tumor cells by interactions with stromal cells, as a critical regulator of extravasation and subsequent metastatic growth in the lung. Third, we will pursue novel preliminary data on the effects of chemotherapy in the metastatic site. Taking advantage of important synergies between the Projects and innovative methodological advances by the Cores, this PPG is well-positioned to make ground-breaking contributions to our understanding of CTC extravasation and grow in the lung, as well as their re-disseminate to tertiary sites. These studies will provide paradigm-shifting insights into the biology of metastasis, with important implications for the clinical treatment of systemic metastatic disease in breast cancer.