Mechanical Induction of the Tumorigenic β-Catenin Pathway by Tumour Growth Pressure in vivo

Abstract

The tumour microenvironment may contribute to tumorigenesis due to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch+Apc+/1638N mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, associated with increased Ret and beta-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by acoustic strain imaging and shear wave elastography. Exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of beta-catenin on Tyr654, which impairs its interaction with the E-cadherin in adherens junctions, and which was followed by beta-catenin nuclear translocation after 15 days. As a consequence, elevated expression of beta-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic beta-catenin pathway, conserved from early embryos beta-catenin dependent mechanical induction of patterning-genes expression, suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.Fernandez-Sanchez, Barbier et al, Nature 2015, Jul 2;523(7558):92-5. http://dx.doi.org/10.1038/nature14329. Epub 2015 May 11.