title: Mechanism of early dissemination and metastasis in Her2+mammary cancer.
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-p38lop-Atf2loTwist1hiE-cadloearly 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-cadloand 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Harper
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Maria Soledad
authors.initials: MS
authors.lastname: Sosa
authors.affiliation: Department of Anatomy and Structural Biology, Integrated Imaging Program, Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York, New York 10461, USA.
authors.forename: David
authors.initials: D
authors.lastname: Entenberg
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Hedayatollah
authors.initials: H
authors.lastname: Hosseini
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Julie F
authors.initials: JF
authors.lastname: Cheung
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Nobre
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Avivar-Valderas
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Chandandaneep
authors.initials: C
authors.lastname: Nagi
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Nomeda
authors.initials: N
authors.lastname: Girnius
authors.affiliation: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Farias
authors.affiliation: Department of Anatomy and Structural Biology, Integrated Imaging Program, Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York, New York 10461, USA.
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
authors.affiliation: Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.|Project group "Personalized Tumour Therapy", Fraunhofer Institute for Toxicology und Experimental Medicine, 93053 Regensburg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Klein
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso