Abstract BS2-1: Ocogenic and microenvironmental signals driving early dissemination, dormancy and metastasis

Abstract

Abstract The mechanisms that produce early-disseminated cancer cells (eDCC) during early stages of breast cancer or that contribute to the development of metastasis from cancer of unknown primary (CUP) are poorly understood. Here we show that HER2+ cancer cells that are present during early stages of cancer before any overt tumors can be detected are highly efficient in systemically disseminating from primary sites. These eDCCs were HER2+/P-p38lo/P-ATF2lo/E-cadherinlo, and were found also in human DCIS samples. Further, eDCC precursors in early lesions activated a Wnt-dependent EMT-like program that was reversed by HER2 or Wnt signaling blockade or p38 activation. Intra-vital imaging of transgenic HER2-CFP mice revealed that eDCC precursors invade the local stroma, intravasate and circulate to target organs, a process that can be stimulated by blocking p38α/β signaling. This process was aided by CD206+/Tie2+ mammary tissue macrophages (MTMs) in a similar way as they regulate mammary branching morphogenesis. We found that macrophages are localized inside the epithelium of early cancer lesions but localize in the stroma of healthy tissue. MTM recruitment depends on upregulation of CCL2 in HER2+ mammary epithelial cells via activation of NFkB. Importantly, samples from patients with DCIS frequently contain intra-epithelial macrophages, correlating with E-Cadherin downregulation. MTMs produce Wnt-1 in response to CCL2 produced by HER2+ early lesion cells and Wnt1 cooperates with the intrinsic oncogene-driven EMT in early cancer cells. Importantly these MTMs contribute to eDCC spread. Surprisingly, although the vast majority of early HER2+ cancer cells are non-tumorigenic, they can spawn eDCCs that remain HER2+/TWIST1+ and dormant in lungs for long periods only to then initiate metastasis. Significantly, depletion of macrophages during early lesion development and before overt tumors appeared, drastically reduced early dissemination and even late metastasis onset. We reveal that during early stages of HER2-driven cancer when dissemination is not thought to occur, HER2 signaling aberrantly activates a side-branching morphogenesis-like program that through macrophage recruitment and cancer cell intrinsic induction of an EMT module causes early dissemination. Our findings reveal that residual cancer may comprise dormant eDCCs with metastasis initiating capacity. We propose our data may lead to changes in our understanding of metastasis onset and how it might be targeted effectively. Citation Format: Aguirre-Ghiso JA. Ocogenic and microenvironmental signals driving early dissemination, dormancy and metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS2-1.