Differential Contributions of RET-isoforms to Tumour Invasion
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Authors
Lian, Eric
Date
Type
thesis
Language
eng
Keyword
RET , Receptor tyrosine kinase , Cancer , Thyroid , Pancreas , Invasion , Migration , GDNF , Isoform
Alternative Title
Abstract
RET is a receptor tyrosine kinase (RTK) which is normally activated at the cell surface by glial cell line-derived neurotrophic factors and plays critical roles during embryogenesis. RET is expressed as two protein isoforms, RET9 and RET51, named for the lengths of their isoform-specific tail sequences. RET also acts as an oncogenic driver in several cancers, and its expression has recently been linked to aggressiveness in multiple tumour types. However, the specific contributions of RET to tumourigenesis are not yet well described. Here we demonstrate that expression of constitutively activated RET in thyroid carcinoma cells contributes to growth, survival, motility and invasiveness, and that loss of RET expression coincides with reduced mesenchymal gene expression with gain of epithelial markers. We showed that activation of wildtype RET in pancreatic adenocarcinomas enhanced directional motility and invasion, suggesting that expression of RET may contribute to invasion towards sources of ligand, such as peripheral nerves. We further showed that RET activation induced invadopodia formation, and that RET interacted with TKS5, an adaptor protein critical for invadopodia formation and function. We observed functional differences between RET isoforms, and demonstrated in both thyroid carcinoma and pancreatic adenocarcinoma cells, that RET51 is more potent than RET9 in enhancing expression of mesenchymal genes, promoting invadopodia formation, cell polarization, cell motility and invasion. Together, our work suggests RET expression, particularly that of RET51, may be useful as a marker for tumour invasiveness in a number of clinically challenging cancers, and that RET may be a potential therapeutic target for treatment of these diseases.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.