| 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 generated an inducible cell line model of EMT to study how induction of EMT affects signaling through proliferation and survival pathways. We found that while cells utilize 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, while after EMT, downregulation of ERBB3 disrupts autocrine signaling to PI3K. Loss of ERBB3 leads to reduced serum-independent proliferation after EMT which can be rescued through reactivation of PI3K by enhanced signaling from p110, ERBB3 re-expression, 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. |
