Author: ["Kathryn L. Harper","Maria Soledad Sosa","David Entenberg","Hedayatollah Hosseini","Julie F. Cheung","Rita Nobre","Alvaro Avivar-Valderas","Chandandaneep Nagi","Nomeda Girnius","Roger J. Davis","Eduardo F. Farias","John Condeelis","Christoph A. Klein","Julio A. Aguirre-Ghiso"]
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Abstract
Two related papers show that cells disseminated from malignant lesions at early time points during tumorigenesis can contribute to metastases at distant organs and provide insights into the molecular basis of dissemination. The origin of metastases in cancer remains an open question. In a pair of linked papers, Christoph Klein, Julio Aguirre-Ghiso and colleagues now show in mouse models that cells disseminated from tumours early in tumorigenesis can contribute to metastases at distant organs at such early time points. Both papers also provide insights into the molecular basis of dissemination, which may be useful as targets to prevent metastasis. Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain 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 than primary tumours or than DCCs from patients with metastases3,4,5. These findings, and those in pancreatic cancer6 and melanoma7 models, 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 and 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 that are capable of forming metastasis after a dormancy phase.Cite this article
Harper, K., Sosa, M., Entenberg, D. et al. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature 540, 588–592 (2016). https://doi.org/10.1038/nature20609 