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Transforming growth factor-β (TGF-β) is a potent inducer of epithelial to mesenchymal transition (EMT). However, it remains elusive about which molecular mechanisms determine the cellular capacity to undergo EMT in response to TGF-β. We have found that both epidermal growth factor receptor (EGFR) overexpression and mutant p53 tumor suppressor genes contribute to the enrichment of an EMT-competent cellular subpopulation among telomerase-immortalized human esophageal epithelial cells during malignant transformation. EGFR overexpression triggers oncogene-induced senescence, accompanied by the induction of cyclin-dependent kinase inhibitors p15INK4B, p16INK4A, and p21. Interestingly, a subpopulation of cells emerges by negating senescence without loss of EGFR overexpression. Such cell populations express increased levels of zinc finger E-box binding (ZEB) transcription factors ZEB1 and ZEB2, and undergo EMT on TGF-β stimulation. Enrichment of EMT-competent cells was more evident in the presence of p53 mutation, which diminished EGFR-induced senescence. RNA interference directed against ZEB resulted in the induction of p15INK4B and p16INK4A, reactivating the EGFR-dependent senescence program. Importantly, TGF-β–mediated EMT did not take place when cellular senescence programs were activated by either ZEB knockdown or the activation of wild-type p53 function. Thus, senescence checkpoint functions activated by EGFR and p53 may be evaded through the induction of ZEB, thereby allowing the expansion of an EMT-competent unique cellular subpopulation, providing novel mechanistic insights into the role of ZEB in esophageal carcinogenesis. Cancer Res; 70(10); 4174–84. ©2010 AACR.

Supplementary Figures 1-6, Table 1 from Epidermal Growth Factor Receptor and Mutant p53 Expand an Esophageal Cellular Subpopulation Capable of Epithelial-to-Mesenchymal Transition through ZEB Transcription Factors

Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor-invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor-invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain-of-loss and loss-of-function experiments. Inhibition of epidermal growth factor receptor signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting the interdependence of two common genetic alterations with periostin function. Collectively, our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (three-dimensional) culture can offer an important tool to discover novel biological effectors in cancer. Cancer Res; 70(13); 5281–92. ©2010 AACR.

Supplementary Figure 4 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Table 2 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Table 1 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Figure 2 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Figure 1 A-C from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer

Supplementary Figure 3 from Periostin, a Cell Adhesion Molecule, Facilitates Invasion in the Tumor Microenvironment and Annotates a Novel Tumor-Invasive Signature in Esophageal Cancer