Mechanism of early dissemination and metastasis in Her2+ mammary cancer

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

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant. Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours. 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 metastases. These findings, and those in pancreatic cancer and melanoma models, indicate that dissemination might occur during the early stages of tumour evolution. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown. 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-p38 lo p-Atf2 lo Twist1 hi E-cad lo 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 Twist1 hi E-cad lo 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.

Original languageEnglish (US)
Pages (from-to)588-592
Number of pages5
JournalNature
Volume540
Issue number7634
DOIs
StatePublished - Dec 22 2016

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Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Organoids
Epithelial-Mesenchymal Transition
Pancreatic Neoplasms
Melanoma
Breast
Phenotype

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Harper, K. L., Sosa, M. S., Entenberg, D. R., Hosseini, H., Cheung, J. F., Nobre, R., ... Aguirre-Ghiso, J. A. (2016). Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature, 540(7634), 588-592. https://doi.org/10.1038/nature20609

Mechanism of early dissemination and metastasis in Her2+ mammary cancer. / Harper, Kathryn L.; Sosa, Maria Soledad; Entenberg, David R.; Hosseini, Hedayatollah; Cheung, Julie F.; Nobre, Rita; Avivar-Valderas, Alvaro; Nagi, Chandandaneep; Girnius, Nomeda; Davis, Roger J.; Farias, Eduardo F.; Condeelis, John S.; Klein, Christoph A.; Aguirre-Ghiso, Julio A.

In: Nature, Vol. 540, No. 7634, 22.12.2016, p. 588-592.

Research output: Contribution to journalArticle

Harper, KL, Sosa, MS, Entenberg, DR, Hosseini, H, Cheung, JF, Nobre, R, Avivar-Valderas, A, Nagi, C, Girnius, N, Davis, RJ, Farias, EF, Condeelis, JS, Klein, CA & Aguirre-Ghiso, JA 2016, 'Mechanism of early dissemination and metastasis in Her2+ mammary cancer', Nature, vol. 540, no. 7634, pp. 588-592. https://doi.org/10.1038/nature20609
Harper KL, Sosa MS, Entenberg DR, Hosseini H, Cheung JF, Nobre R et al. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature. 2016 Dec 22;540(7634):588-592. https://doi.org/10.1038/nature20609
Harper, Kathryn L. ; Sosa, Maria Soledad ; Entenberg, David R. ; Hosseini, Hedayatollah ; Cheung, Julie F. ; Nobre, Rita ; Avivar-Valderas, Alvaro ; Nagi, Chandandaneep ; Girnius, Nomeda ; Davis, Roger J. ; Farias, Eduardo F. ; Condeelis, John S. ; Klein, Christoph A. ; Aguirre-Ghiso, Julio A. / Mechanism of early dissemination and metastasis in Her2+ mammary cancer. In: Nature. 2016 ; Vol. 540, No. 7634. pp. 588-592.
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