Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Ichan School of Medicine at Mount Sinai
Abstract: Clinical evidence suggests that improved outcomes within the first 5 years are due to advances in early detection, surgery and anti-proliferative therapies. This success has led to patients living longer. Nevertheless, they still die from late cancer recurrence. While a number of mechanisms may contribute, growing evidence suggests that late relapse may be due to the ability of disseminated cancer cells (DCCs) to survive in a quiescent or dormant state and evade therapies. DCCs are thought to originate from invasive primary lesions, but it is now recognized that early-evolved lesions can also generate DCCs. The mechanisms that produce early-disseminated cancer cells (eDCC) during early stages of breast cancer evolution are poorly understood. Here we show that HER2+ cancer cells in mammary intraepithelial neoplasias (MIN), are highly efficient in systemically disseminating from primary sites. These eDCCs were HER2+/P-ATF2lo/E-cadherinlo, and were found also in human DCIS samples. Further, eDCC precursors in MIN lesions underwent a Wnt-dependent EMT that was reversed by HER2 or Wnt signaling blockade. Intra-vital imaging of transgenic HER2-CFP MIN lesions revealed that eDCC precursors invade the local stroma, intravasate and circulate to target organs. This process was aided by macrophages in similar way as they regulate mammary branching morphogenesis. We found that macrophages are localized inside the epithelium of pre-malignant lesions but localize in the stroma of healthy tissue. Macrophage recruitment depends on upregulation of CCL2 in HER2+ mammary epithelial cells via activation of NFkB. Importantly, samples from patients with DCIS frequently contained intra-epithelial macrophages, correlating with E-Cadherin downregulation. Macrophage invasion into ducts disrupted the myoepithelium and further supported the oncogene-driven EMT-like response in luminal cells and their spread. Surprisingly, although the vast majority of eDCCs are non-proliferative, they can still initiate metastasis. However, depletion of macrophages from pre-malignant HER2+ lesions drastically reduces early dissemination and late metastasis. We reveal that during a stage when HER2 still does not fuel proliferation, it aberrantly activates a side-branching morphogenetic program that through macrophage recruitment and an EMT-like response causes early dissemination. That eDCCs carry latent metastatic initiating capacity cancer changes our understanding of metastasis onset and how it might be targeted effectively. For example, if immune therapies depend on a high mutational load, eDCCs may evade immune detection.
Friday, April 15, 2016
Host: Peter Kuhn