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Nature. 2015 Jul 2;523(7558):92-5. doi: 10.1038/nature14329. Epub 2015 May 11.

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

Author information

1
Institut Curie, Centre de Recherche, PSL Research University, CNRS UMR 168, Physicochimie Curie Mechanics and Genetics of Embryonic and Tumour Development, INSERM, Fondation Pierre-Gilles de Gennes, F-75005 Paris, France.
2
UPMC, Sorbonne Universités, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystèmes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France.
3
Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France.
4
Sorbonne Universités, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France.
5
CNRS UMR3666/INSERM U1143, Endocytic Trafficking and Therapeutic Delivery, Institut Curie, Centre de Recherche, F-75005 Paris, France.
6
Bioinformatic platform, U900, Institut Curie, MINES ParisTech, F-75005 Paris, France.
7
Next-generation sequencing platform, Institut Curie, F-75005 Paris, France.
8
CNRS UMR 8612, Laboratoire Physico-Chimie des Systèmes Polyphasés, Institut Galien Paris-Sud, LabEx LERMIT, Faculté de Pharmacie, Université Paris-Sud, 92 296 Châtenay-Malabry, France.
9
CNRS UMR 3215/INSERM U934, Unité de Génétique et Biologie du Développement, Notch Signaling in Stem Cells and Tumors, Institut Curie, Centre de Recherche, F-75005 Paris, France.
10
CNRS UMR144, Compartimentation et dynamique cellulaires, Morphogenesis and Cell Signalling Institut Curie, Centre de Recherche, F-75005 Paris, France.

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.

PMID:
25970250
DOI:
10.1038/nature14329
[Indexed for MEDLINE]

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