Abstract A56: Identification of an ErbB2+ early disseminating cancer cell subpopulation with metastatic potential

Abstract

Abstract Recent clinical evidence suggests that cells are capable of disseminating from pre-invasive breast cancer lesions. It has been proposed that these early disseminating cancer cells (eDCCs) lodge into secondary sites, enter a state of dormancy, escape conventional therapy, and potentially evolve through different pathways from the primary tumor to form metastases. However, the mechanisms that endow these early cancer cells to disseminate and their behavior in target organs remain unknown. Here we show that ErbB2+ early cancer cells, while non-tumorigenic are highly efficient in disseminating. While a majority of these eDCCs remain dormant in target organs they are still endowed with a metastatic capacity. We identified an ErbB2HIGH/p38LOW/E-cadherinLOW/PRHI population of early cancer cells, which undergo a Wnt-dependent EMT and disseminate. Based on this signature we propose that these early cancer cells tap into motility programs similar to what is seen during branching morphogenesis (PRHI/WntHI/p38LOW) in order to disseminate. Using intra-vital imaging of transgenic ErbB2-T-CFP pre-malignant lesions we imaged this process at high resolution revealing that ErbB2HIGH/p38LOW/E-cadherinLOW cells display activate cancer cell motility, invadopodia formation and intravasation capacity. This correlated with CK8/18+/HER2+ circulating cancer cells as well as eDCCs in the lung and bone marrow of mice, a process that was enhanced following 2 weeks of systemic p38α/β inhibition. We conclude that during stages previously considered non-invasive, some HER2+ cancer cells can aberrantly activate an invasive morphogenetic program causing early dissemination that is normally restricted by active p38 signaling. These eDCCs carry latent metastatic initiating capacity and may contribute to relapse, altering our understanding of metastasis onset and how it might be targeted effectively. Citation Format: Kathryn Harper, Maria Soledad Sosa, Hedayatollah Hosseini, Alvaro Avivar Valderas, Chandandaneep Nagi, Roger Davis, Christoph Klein, David Entenberg, John Condeelis, Eduardo Farias, Julio Aguirre-Ghiso. Identification of an ErbB2+ early disseminating cancer cell subpopulation with metastatic potential. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A56.