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Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.

Abstract：

:The tumour microenvironment may contribute to tumorigenesis owing 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, which is associated with increased Ret and β-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 ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of β-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by β-catenin nuclear translocation after 15 days. As a consequence, increased expression of β-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 β-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.

journal_name

Nature

journal_title

Nature

authors

Fernández-Sánchez ME,Barbier S,Whitehead J,Béalle G,Michel A,Latorre-Ossa H,Rey C,Fouassier L,Claperon A,Brullé L,Girard E,Servant N,Rio-Frio T,Marie H,Lesieur S,Housset C,Gennisson JL,Tanter M,Ménager C,Fre S,Rob

doi

10.1038/nature14329

subject

Has Abstract

pub_date

2015-07-02 00:00:00

pages

92-5

issue

7558

eissn

0028-0836

issn

1476-4687

pii

nature14329

journal_volume

523

pub_type

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Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.