title: 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.
authors.affiliation: 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.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Fernández-Sánchez
authors.affiliation: 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.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Barbier
authors.affiliation: 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.
authors.forename: Joanne
authors.initials: J
authors.lastname: Whitehead
authors.affiliation: UPMC, Sorbonne Universités, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystèmes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Béalle
authors.affiliation: UPMC, Sorbonne Universités, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystèmes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Michel
authors.affiliation: Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France.
authors.forename: Heldmuth
authors.initials: H
authors.lastname: Latorre-Ossa
authors.affiliation: Sorbonne Universités, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Rey
authors.affiliation: Sorbonne Universités, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Fouassier
authors.affiliation: Sorbonne Universités, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Claperon
authors.affiliation: CNRS UMR3666/INSERM U1143, Endocytic Trafficking and Therapeutic Delivery, Institut Curie, Centre de Recherche, F-75005 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Brullé
authors.affiliation: Bioinformatic platform, U900, Institut Curie, MINES ParisTech, F-75005 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Girard
authors.affiliation: Bioinformatic platform, U900, Institut Curie, MINES ParisTech, F-75005 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Servant
authors.affiliation: Next-generation sequencing platform, Institut Curie, F-75005 Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rio-Frio
authors.affiliation: 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.
authors.forename: Hélène
authors.initials: H
authors.lastname: Marie
authors.affiliation: 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.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Lesieur
authors.affiliation: Sorbonne Universités, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.affiliation: Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Gennisson
authors.affiliation: Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Tanter
authors.affiliation: UPMC, Sorbonne Universités, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystèmes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Ménager
authors.affiliation: 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.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fre
authors.affiliation: CNRS UMR144, Compartimentation et dynamique cellulaires, Morphogenesis and Cell Signalling Institut Curie, Centre de Recherche, F-75005 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Farge
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D003110:Colonic Neoplasms / Q000503:physiopathology*; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059346:Magnets; D008297:Male; D053768:Metal Nanoparticles; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011312:Pressure; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D051176:beta Catenin; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse