The coordinated regulation of developmental gene expression and morphogenetic movements during embryogenesis relies on feedback between these two systems. Activation and maintenance of the expression of genes critical for embryogenesis can be dependent on mechanical induction triggered by morphogenetic movements within the embryo. This has been demonstrated by the host laboratory for the twist-dependent invagination of the anterior foregut in Drosophila, in response to compression caused by germ band extension.
The twist pathway is activated by the mechano-sensitive translocation of Armadillo to the nucleus, which in turn initiates gene expression patterns triggering further morphogenetic movements, in part via inhibition of the adhesion protein E-cadherin. Homologous pathways act at the endothelial-mesenchymal transition of mammalian tumours, with nuclear translocation of B-catenin (mammalian Armadillo homologue), down-regulation of E-cadherin, and upregulation of twist. This pathway therefore represents a critical control point for regulation of tumour metastasis. I propose to extend the investigation of mechano-sensitive twist expression to mouse and human cancers, to determine whether mechanical strain caused by tumour growth is a contributor to metastasis.
Initial studies will make use of a series of mouse mutants, which develop a controlled spectrum of stages of gastrointestinal cancer, and parallel studies will be carried out in clinical breast tumour tissues. Should a positive correlation be determined between endogenous or exogenous mechanical pressure and tumour metastasis, these studies could have serious implications for the safety and efficacy of screening mammography.
Field of science
- /medical and health sciences/clinical medicine/cancer/colorectal cancer
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
- /medical and health sciences/clinical medicine/cancer/breast cancer
- /natural sciences/biological sciences/genetics and heredity/mutation
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