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Mechanism of early dissemination and metastasis in Her2+ mammary cancer

: Harper, Kathryn L.; Sosa, Maria Soledad; Entenberg, David; Hosseini, Hedayatollah; Cheung, Julie F.; Nobre, Rita; Avivar-Valderas, Alvaro; Nagi, Chandandaneep; Girnius, Nomeda; Davis, Roger J.; Farias, Eduardo F.; Condeelis, John; Klein, Christoph A.; Aguirre-Ghiso, Julio A.


Nature 540 (2016), Nr.7634, S.588-592
ISSN: 0028-0836
ISSN: 1476-4687
Fraunhofer ITEM ()

Metastasis is the leading cause of cancer-related deaths and these lesions develop from disseminated cancer cells (DCCs) that canremain dormant1. Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours2.However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities thanprimary tumours or than DCCs from patients with metastases3–5. These findings, and those in pancreatic cancer6 and melanoma7models, indicate that dissemination might occur during the early stages of tumour evolution3,8,9. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown8. Here we show that in early lesions in mice, before any apparent primary tumour masses are detected, there is a sub-population of Her2+p-p38lop-Atf2loTwist1hiE-cadlo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2+ eDCC precursors invaded locally, intravasated and lodged in target organs. Her2+ eDCCs activated a Wnt-dependent epithelial–mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1hiE-cadlo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs capable of forming metastasis after a dormancy phase.