MECHANO · sensitive gene expression in embryogenesis and tumourigenesis
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-05-01 → 2008-04-30
- EU contribution
- €159,353
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - MECHANO (Mechano-sensitive gene expression in embryogenesis and tumourigenesis)
Currently each of us has about a 40 % risk of developing cancer in our lifetime. Colorectal cancer is the third most prevalent cancer in the western world, and treatment options are limited. Mutations in the APC gene are found in the majority of colon tumours, but mutation alone is not sufficient to produce disease: non-genetic factors also play a major role, but are not yet well understood. By studying mice which have a high incidence of cancer due to an inherited APC mutation, we have demonstrated that mechanical pressure can induce expression of the genes Myc and Twist, which are known to play an important role in the initiation of cancer and in the metastasis of tumours to other organs of the body. This mechanosensitive gene expression is not induced in the colon tissue of normal mice, showing that genetic and mechanical factors can cooperate to promote tumourgenesis. The digestive tract experiences regular variations in mechanical strain due to peristalisis and intestinal transit, and our work suggests that if a mutation in APC has occurred, the tissue may become hypersensitive to these normal cues, and respond inappropriately by activating tumour-promoting genes. We have shown that when cells of the colon sense mechanical strain, proteins of the Src kinase family are activated, and these in turn activate beta-catenin, a protein which acts as the main regulator of development and renewal of the digestive tract, through its ability to switch from a structural role at the junctions between neighbouring cells, to a transcriptional regulator in the cell nucleus, where it has the capacity to induce expression of many different target genes. Importantly, we have shown that the mechanosensitive expression of Myc and Twist can be inhibited pharmacologically using the drugs PP1 or PP2, which specifically target the Src kinase family. When APC mutant colon is mechanically strained in the presence of these drugs, Src is not activated, so the signal is not relayed to the nucleus by beta-catenin, and Myc and Twist remain silent. Therefore this research has shown not only that endogenous mechanical cues may be one type of environmental factor which, together with genetic mutation, drive colon cancer development, but that this inappropriate mechanosensitive pathway can be inhibited with existing drugs.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- INSTITUT CURIE · PARISCoordinatorFrance
Links
Data: CORDIS, © European Union