Emmanuel Farge (Institut Curie, France), Mechanotransduction in development, evolution and cancer

Emmanuel Farge is Research Director at INSERM, Mechanics and Genetics of Embryonic and Tumoral Development group, UMR 168 Physico-Chimie Curie, Institut Curie –  Paris Sciences et Lettres Research University.

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Mechanotransduction in development: from mesoderm mechanotransductive evolutionary origins to tumourigenic mechanical induction

Bilaterians are complex organisms, characterized by the existence of a mesoderm tissue from which most of animal complex organs develop. Mesoderm emerged 570 millions years ago from cnidarians that are characterized by and ectoderm and an endoderm only. The lack of conservation of biochemical signalling proteins upstream of early embryonic mesoderm differentiation across bilaterians prevents to answer the question of the signal having been at the evolutionary origin of mesoderm emergence and complex animals. We found the mechanical phosphorylation of the Y654 site of b-catenin at junctions by the first morphogenetic movements of embryogenesis, leading its release to the cytoplasm and nucleus, as involved and conserved in earliest mesoderm differentiation in the vertebrate zebrafish and un-vertebrate Drosophila, two species having directly diverged from the last common ancestor of bilaterians.

We thus proposed mechanical activation of b-catenin signalling as having been involved in the evolutionary transition to mesoderm differentiation and complex animals evolutionary emergence¹. The underlying molecular mechanism consists in the mechanical opening of the Y654-D665 major site of interaction between b-catenin and E-cadherin, favoring Y654-b-catenin phosphorylation by Src42A, which mechanotransductively impairs the interaction and leads to b-catenin release from the junctions².

Extended to tumour biology and cancer progression, we found mechanical activation of b-catenin as conserved in mice and involved in the mechanical activation of tumorigenic biochemical pathways, in the healthy epithelium compressed by the neighbouring tumour, in response to tumour growth pressure in vivo ^3-5.

Upstream of the first morphogenetic movement of embryogenesis, we found additional mechanotransductive cues, stimulated by mesodermal apex soft pulsations, triggering the medio-apical stabilisation of Myo-II leading to mesoderm invagination, namely to gastrulation, in drosophila embryos⁶.

1     Brunet, T. et al. Evolutionary conservation of early mesoderm specification by mechanotransduction in Bilateria. Nature communications 4, doi:10.1038/ncomms3821 (2013).

2     Roper, J. C. et al. The major beta-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo. eLife 7, doi:10.7554/eLife.33381 (2018).

3     Whitehead, J. et al. Mechanical factors activate beta-catenin-dependent oncogene expression in APC mouse colon. HFSP journal 2, 286-294, doi:10.2976/1.2955566 (2008).

4     Fernandez-Sanchez, M. E., Barbier, S. & al., e. Mechanical induction of the tumorogenic β-catenin pathway by tumour growth pressure. Nature (In press).

5     Fernandez-Sanchez, M. E., Brunet, T., Roper, J. C. & Farge, E. Mechanotransduction’s Impact in Animal Development, Evolution, and Tumorigenesis. Annu Rev Cell Dev Biol, doi:10.1146/annurev-cellbio-102314-112441 (2015).

6     Mitrossilis, D. et al. Mechanotransductive cascade of Myo-II-dependent mesoderm and endoderm invaginations in embryo gastrulation. Nature communications 8, 13883, doi:10.1038/ncomms13883 (2017).