title: Mechanical factors activate beta-catenin-dependent oncogene expression in APC mouse colon.
abstract: beta-catenin acts as a critical regulator of gastrointestinal homeostasis through its control of the Wnt signaling pathway, and genetic or epigenetic lesions which activate Wnt signaling are the primary feature of colon cancer. beta-catenin is also a key element of mechanotranscription pathways, leading to upregulation of master developmental gene expression during Drosophila gastrulation, or regulating mammalian bone development and maintenance. Here we investigate the impact of mechanical stimulation on the initiation of colon cancer. Myc and Twist1, two oncogenes regulated through beta-catenin, are expressed in response to transient compression in APC deficient (APC(1638N+)) colon tissue explants, but not in wild-type colon explants. Mechanical stimulation of APC(1638N+) tissue leads to the phosphorylation of beta-catenin at tyrosine 654, the site of interaction with E-cadherin, as well as to increased nuclear localization of beta-catenin. The mechanical activation of Myc and Twist1 expression in APC(1638N+) colon can be prevented by blocking beta-catenin phosphorylation using Src kinase inhibitors. Microenvironmental signals are known to cooperate with genetic lesions to promote the nuclear beta-catenin accumulation which drives colon cancer. Here we demonstrate that when APC is limiting, mechanical strain, such as that associated with intestinal transit or tumor growth, can be interpreted by cells of preneoplastic colon tissue as a signal to initiate a beta-catenin dependent transcriptional program characteristic of cancer.
authors.forename: Joanne
authors.initials: J
authors.lastname: Whitehead
authors.forename: Danijela
authors.initials: D
authors.lastname: Vignjevic
authors.forename: Claus
authors.initials: C
authors.lastname: Fütterer
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Beaurepaire
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Farge