title: A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages.
abstract: The cell-biological program termed the epithelial-mesenchymal transition (EMT) confers on cancer cells mesenchymal traits and an ability to enter the cancer stem cell (CSC) state. However, the interactions between CSCs and their surrounding microenvironment are poorly understood. Here we show that tumour-associated monocytes and macrophages (TAMs) create a CSC niche through juxtacrine signalling with CSCs. We performed quantitative proteomic profiling and found that the EMT program upregulates the expression of CD90, also known as Thy1, and EphA4, which mediate the physical interactions of CSCs with TAMs by directly binding with their respective counter-receptors on these cells. In response, the EphA4 receptor on the carcinoma cells activates Src and NF-κB. In turn, NF-κB in the CSCs induces the secretion of a variety of cytokines that serve to sustain the stem cell state. Indeed, admixed macrophages enhance the CSC activities of carcinoma cells. These findings underscore the significance of TAMs as important components of the CSC niche.
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA.
authors.forename: Haihui
authors.initials: H
authors.lastname: Lu
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Karl R
authors.initials: KR
authors.lastname: Clauser
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA [3] Genome Institute of Singapore, 60 Biopolis Street Singapore 138672, Singapore.
authors.forename: Wai Leong
authors.initials: WL
authors.lastname: Tam
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3] University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Fröse
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Elinor Ng
authors.initials: EN
authors.lastname: Eaton
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.affiliation: 1] Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA [2] Department of Cardiothoracic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Vera S
authors.initials: VS
authors.lastname: Donnenberg
authors.affiliation: Magee-Womens Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhargava
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] MIT Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*
chemical_list: D016328:NF-kappa B