EMT-induced stemness and tumorigenicity are fueled by the EGFR/Ras pathway.
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.
The Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Dominic Chih-Cheng
DC
Voon
Huajing
H
Wang
Jason Kin Wai
JK
Koo
Juin Hsien
JH
Chai
Yit Teng
YT
Hor
Tuan Zea
TZ
Tan
Yeh-Shiu
YS
Chu
Seiichi
S
Mori
Yoshiaki
Y
Ito
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)