title: Epithelial-to-mesenchymal transition rewires the molecular path to PI3K-dependent proliferation.
abstract: Tumors showing evidence of epithelial-to-mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. Heterogeneity along the EMT spectrum is observed between and within tumors. To develop effective therapeutics, a mechanistic understanding of how EMT affects the molecular requirements for proliferation is needed. We found that although cells use phosphoinositide 3-kinase (PI3K) for proliferation in both the epithelial and mesenchymal states, EMT rewires the mechanism of PI3K pathway activation. In epithelial cells, autocrine ERBB3 activation maintains PI3K signaling, whereas after EMT, downregulation of ERBB3 disrupts autocrine signaling to PI3K. Loss of ERBB3 leads to reduced serum-independent proliferation after EMT that can be rescued through reactivation of PI3K by enhanced signaling from p110α, ERBB3 reexpression, or growth factor stimulation. In vivo, we demonstrate that PIK3CA expression is upregulated in mesenchymal tumors with low levels of ERBB3. This study defines how ERBB3 downregulation after EMT affects PI3K-dependent proliferation.
  
  
  CONCLUSIONS
  This study describes a mechanism through which EMT transition alters the proliferative potential of cells by modulating ERBB3 expression. Furthermore, it demonstrates the potential for multiple molecular routes to drive proliferation in different cell states, illustrating how changes in EMT status can rewire signaling upstream of cell proliferation.
authors.affiliation: 1Helen Diller Family Comprehensive Cancer Center; 2Biomedical Sciences Graduate Program, University of California San Francisco; and 3California Institute for Quantitative Biosciences, San Francisco, California.
authors.forename: Megan B
authors.initials: MB
authors.lastname: Salt
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt