Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells

Samit Chatterjee, Laurie Seifried, Michael E. Feigin, Don L. Gibbons, Claudio Scuoppo, Wei Lin, Zain H. Rizvi, Evan Lind, Dilan Dissanayake, Jonathan Kurie, Pam Ohashi, Senthil K. Muthuswamy

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFα induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines.

Original languageEnglish (US)
Article numbere34343
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 18 2012
Externally publishedYes

Fingerprint

Cell Polarity
oncogenes
Oncogenes
epithelial cells
Epithelial Cells
Proteins
proteins
carcinoma
Chemical activation
cytokines
protein synthesis
cells
phenotypic plasticity
Tissue
Cytokines
interleukin-6
Carcinoma
collagen
aggression
cell polarity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Chatterjee, S., Seifried, L., Feigin, M. E., Gibbons, D. L., Scuoppo, C., Lin, W., ... Muthuswamy, S. K. (2012). Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. PLoS One, 7(4), [e34343]. https://doi.org/10.1371/journal.pone.0034343

Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. / Chatterjee, Samit; Seifried, Laurie; Feigin, Michael E.; Gibbons, Don L.; Scuoppo, Claudio; Lin, Wei; Rizvi, Zain H.; Lind, Evan; Dissanayake, Dilan; Kurie, Jonathan; Ohashi, Pam; Muthuswamy, Senthil K.

In: PLoS One, Vol. 7, No. 4, e34343, 18.04.2012.

Research output: Contribution to journalArticle

Chatterjee, S, Seifried, L, Feigin, ME, Gibbons, DL, Scuoppo, C, Lin, W, Rizvi, ZH, Lind, E, Dissanayake, D, Kurie, J, Ohashi, P & Muthuswamy, SK 2012, 'Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells', PLoS One, vol. 7, no. 4, e34343. https://doi.org/10.1371/journal.pone.0034343
Chatterjee, Samit ; Seifried, Laurie ; Feigin, Michael E. ; Gibbons, Don L. ; Scuoppo, Claudio ; Lin, Wei ; Rizvi, Zain H. ; Lind, Evan ; Dissanayake, Dilan ; Kurie, Jonathan ; Ohashi, Pam ; Muthuswamy, Senthil K. / Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. In: PLoS One. 2012 ; Vol. 7, No. 4.
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