EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway

Abstract

Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 −/− p53 −/− murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.

Induction of Epithelial-Mesenchymal Transition via Activation of Epidermal Growth Factor Receptor Contributes to Sunitinib Resistance in Human Renal Cell Carcinoma Cell Lines

“…EGFR signaling is linked to maintenance of the EMT status in cancer cells (Voon et al, 2013). Although sunitinib targets various RTKs, the association between sunitinib and EGFR has not yet been investigated.…”

Single nucleotide polymorphisms in AREG and EREG are prognostic biomarkers in locally advanced gastric cancer patients after surgery with curative intent

“…Recent in vitro studies have revealed a critical role of EGFR signaling for stemness in GC cell lines [33]. This role for EGFR signaling is supported by the observation that EGF-receptor expression and the expression levels of the EGFR ligands AREG and EREG are also associated with prognosis and relapse prediction [15].…”

Expression of tripartite motif-containing protein 28 in primary breast carcinoma predicts metastasis and is involved in the stemness, chemoresistance, and tumor growth

“…Recent studies described that chemoresistance was associated with self-renewal and anchorageindependent properties of cancer cells along with up-regulation of EMT markers and down-regulation of EMT markers. 15,16 In this report, we present evidence for differential expression of genes in a novel network centered on TRIM28 (a member of E3 ubiquitin ligase family) in cohorts of breast cancer patients belonging to groups who proceeded to metastasis or remained disease free for a 5-year period. Furthermore, we show functional significance of TRIM28 by short hairpin RNA (shRNA) knockdown experiments in two breast cancer cell lines.…”