Project Summary
In our previous work, we showed that ErbB expression and dimerization guides treatment responses of esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) to EGFR- and/or HER2-targeted inhibitors. In a model system, we induced cell invasion of non-neoplastic (non-invasive) esophageal epithelial cells by controlled activation of HER2 homo- and HER2/HER3 heterodimers. These events were paralleled in situ and in vitro by Signal Transducer and Activator of Transcription (STAT) and Src / Src-family kinase (SFK) signalling. We now ask: 1) how does Src/SFK signalling influence cell migration and invasion? Here we will examine a potential interaction of Src with Aurora-A; 2) are there any “internal” counter-regulatory mechanisms to ErbB- and Src-associated signalling involved in esophageal cell motility? Here we will explore the effect of the metastasis suppressor KAI1/CD82 and (E-)Cadherin/(ß-)Catenin; and 3) are there any “external” influences on ErbB- and Src-associated esophageal cell migration and invasion? Here we will examine the effect of the tumor milieu’s cell-context/morphology on YAP/TAZ Hippo pathway activation in contact inhibition and interference with ErbB-associated signalling. Together, these experiments shall specify the contribution of ErbB receptors and their signalling pathways to the pathobiology of early (i.e. invasion) and advanced (i.e. metastasis) esophageal cancers and the mechanism of action, respective resistance to ErbB targeting inhibitors.
