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Mechano-sensitive gene expression in embryogenesis and tumourigenesis

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.