Abstract IA24: A stem cell program in early human metastatic breast cancer cells

Abstract

Abstract Metastasis is the process that leads to the poor prognosis in breast cancer. Understanding the processes involved in the initiation and progression of metastasis is critical for developing new preventative and therapeutic strategies. One hypothesis states that metastases arise from rare tumor cells that resemble stem cells in their ability to initiate and propagate tumors. In this study we used single-cell analysis to demonstrate that the initial disseminating metastatic cells resemble stem cells in their gene expression. We exploited patient-derived xenograft (PDX) models of human breast cancer to analyze metastatic cells in peripheral tissues. We developed a highly sensitive FACS-based assay to isolate and enumerate these metastatic cells. The primary tumor cells were heterogeneous and expressed high levels of luminal differentiation genes The metastatic cells from tissues with a low metastatic burden showed increased expression of stem cell, EMT, pro-survival, and dormancy-associated genes and differential expression of genes depending on the peripheral tissue. In contrast, in macrometastases, the cells were similar to primary tumor cells. The stem cell-like metastatic cells from low-burden tissues had significant tumor-initiating capacity upon transplantation, and differentiated to produce cancer cells with luminal gene expression. As the metastases progressed to a high metastatic burden the tumor cells showed increased expression of cMYC and proliferation-related genes. Our studies suggest that metastases are initiated by cells with stem cell character that upon proliferation and differentiation produce advanced metastatic disease and a poor outcome.