TY - JOUR
T1 - Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast
AU - Scheel, Christina
AU - Eaton, Elinor Ng
AU - Li, Sophia Hsin Jung
AU - Chaffer, Christine L.
AU - Reinhardt, Ferenc
AU - Kah, Kong Jie
AU - Bell, George
AU - Guo, Wenjun
AU - Rubin, Jeffrey
AU - Richardson, Andrea L.
AU - Weinberg, Robert A.
N1 - Funding Information:
We thank Brian Bierie, Thijn Brummelkamp, Sunny Gupta, Katharina Leuchte, Julia Rastelli, Andreas Scheel, Scott Valastyan, and Irene Wuethrich for critical reading of the manuscript, members of the Weinberg lab for discussion, John Stingl for protocols, the Whitehead Microarray and Flow Cytometry Cores, and the W.M. Keck Microscopy Facility for technical support. This research was supported by the National Institutes of Health/National Cancer Institute (R.A.W.; CA12515 and DE020817), Massachusetts Institute of Technology Ludwig Center for Molecular Oncology (R.A.W.), Ludwig Fellowship for Metastasis Research (C.S.), Breast Cancer Research Foundation (A.L.R. and R.A.W.), Harvard Breast Cancer SPORE (A.L.R. and R.A.W.), Department of Defense Breast Cancer Research Program Idea Award (R.A.W.), and Samuel Waxman Foundation (R.A.W.). C.S. and R.A.W. are inventors on a patent application in part based on findings detailed in this manuscript.
PY - 2011/6/10
Y1 - 2011/6/10
N2 - The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of motility, invasiveness, and self-renewal traits. During both normal development and tumor pathogenesis, this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment. The signals that are responsible for inducing an EMT and maintaining the resulting cellular state have been unclear. We describe three signaling pathways, involving transforming growth factor (TGF)-β canonical and noncanonical Wnt signaling, that collaborate to induce activation of the EMT program and thereafter function in an autocrine fashion to maintain the resulting mesenchymal state. Downregulation of endogenously synthesized inhibitors of autocrine signals in epithelial cells enables the induction of the EMT program. Conversely, disruption of autocrine signaling by added inhibitors of these pathways inhibits migration and self-renewal in primary mammary epithelial cells and reduces tumorigenicity and metastasis by their transformed derivatives.
AB - The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of motility, invasiveness, and self-renewal traits. During both normal development and tumor pathogenesis, this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment. The signals that are responsible for inducing an EMT and maintaining the resulting cellular state have been unclear. We describe three signaling pathways, involving transforming growth factor (TGF)-β canonical and noncanonical Wnt signaling, that collaborate to induce activation of the EMT program and thereafter function in an autocrine fashion to maintain the resulting mesenchymal state. Downregulation of endogenously synthesized inhibitors of autocrine signals in epithelial cells enables the induction of the EMT program. Conversely, disruption of autocrine signaling by added inhibitors of these pathways inhibits migration and self-renewal in primary mammary epithelial cells and reduces tumorigenicity and metastasis by their transformed derivatives.
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U2 - 10.1016/j.cell.2011.04.029
DO - 10.1016/j.cell.2011.04.029
M3 - Article
C2 - 21663795
AN - SCOPUS:79958265710
SN - 0092-8674
VL - 145
SP - 926
EP - 940
JO - Cell
JF - Cell
IS - 6
ER -