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Mechanotransduction in animal development, evolution and tumorigenesis

Mechanotransduction consists in the translation of mechanical strains into biochemical cues. The first demonstration of the impact of mechanotransduction in the regulation of physiological processes in vivo came from the discovery of the mechanical activation of primary patterning pathways that control early embryonic development, in response to the morphogenetic movements of gastrulation. It was additionally found that this process could have been involved in ancient organisms’ major evolutionary transitions, such as mesoderm emergence in the first common ancestor of bilaterians. Within the context of adult animal tissues, recent studies demonstrate the tumorigenic impact of tissue growth pressure on neighbouring healthy tissues through the activation of such conserved mechanotransductive cues1,2.

It has been known since three decades that cells actively respond to mechanical strains by adapting their mechanical characteristics to their physical environment (including substrate stiffness and direct mechanical strain-deformation), through a mechanical regulation of both active cytoskeleton rearrangements and cell division rate, in cell culture3-6.  In the early 2000’s, we have demonstrated that mechanical strain deformation also controls functional cell differentiation, both ex-vivo in cell culture7 and in vivo in early embryos in response to gastrulation induced mechanical strains8. In the former case, both cell size and substrate stiffness constraints were additionally found in stem cells as involved in this response9,10.

To test the physiological impact of mechanotransductive processes in vivo in a systematic manner, we developed innovative tools based on the magnetization of tissues, to apply physiological mechanical forces of pure physical origin in response to the application of quantified magnetic field gradients11. Applied to Drosophila and zebrafish early embryos, these tools  are able to rescue the mechanical strains lacking in mutant or pharmacologically treated gastrulation defective embryos. This allowed to test and demonstrate that Drosophila functional endodermal differentiation is mechanically induced by gastrulation morphogenetic movements, as well as mesoderm differentiation in both the arthropod Drosophila and the vertebrate zebrafish embryos (Figure A)11,12.

Mechanical induction of the β-catenin dependent early mesoderm differentiation in the zebrafish embryo, at the onset of epiboly
Figure A: Mechanical induction of the β-catenin dependent early mesoderm differentiation in the zebrafish embryo, at the onset of epiboly

In both species, such process is initiated by the mechanical induction of the phosphorylation of the highly evolutionary conserved Y654 site of beta-catenin. Phosphorylation of Y654 is known to lead to beta-catenin release from junctions to the nuclei, and to favour the downstream transcription of its mesodermal target genes*.

Thus, in addition to demonstrate the involvement of mechanical strains associated to morphogenetic movements in the regulation of the functional genetic cascade of early embryos major differentiations, these findings allowed to propose an element of answer to the fundamental opened question of the origins of mesoderm evolutionary emergence in the Evo-Devo field, in suggesting “mechanical induction” as having been involved in mesoderm emergence in the first common ancestor to bilaterians (from which Drosophila and zebrafish directly diverged)12.

Adapting our magnetic methodology to adult animals, we could mimic the 1kPa pressure exerted by tumour growth into the colon by magnetizing the conjunctive tissue cells of the colonic epithelium, and locating a small and strong magnet under-skin in front of the distal colon. This led to the mechanical induction of the phosphorylation of the Y654 beta-catenin site again, which activated, in non-tumorigenic healthy tissues, an oncogenic response leading to hyper-proliferation, and tumorigenesis in the presence of a predisposing mutation. Such mechanical reactivation of an early embryogenesis differentiation mechanosensitive pathway, which is tumorigenic in adult tissues,  reveals this process as involved in the amplification of tumorigenic pathways in healthy tissues, in response to their compression by their neighbouring tumorigenic tissues (Figure B)2.

Mechanical induction of the β-catenin tumorigenic pathway in healthy epithelia in response to tumour growth pressure, in vivo.
Figure B: Mechanical induction of the β-catenin tumorigenic pathway in healthy epithelia in response to tumour growth pressure, in vivo.

*Interestingly, the mechanosensitivity of the beta-catenin pathway has now been found as involved in many diverse biological contexts (Farge, Current Bioloy, 2003; Sens et al, Endocrinology, 2008; Whitehead et al, HSFPJ, 2008; Khan et al, Dev Cell, 2009; Samuel et al, Cancer Cell, 2011; Benham-Pyle, Science, 2015).

Emmanuel Farge


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  2. Fernandez-Sanchez, M. E. et al. Mechanical induction of the tumorigenic beta-catenin pathway by tumour growth pressure. Nature 523, 92-95, doi:10.1038/nature14329 (2015).
  3. Gospodarowicz, D., Greenburg, G. & Birdwell, C. R. Determination of cellular shape by the extracellular matrix and its correlation with the control of cellular growth. Cancer Res 38, 4155-4171 (1978).
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  7. Rauch, C., Brunet, A. C., Deleule, J. & Farge, E. C2C12 myoblast/osteoblast transdifferentiation steps enhanced by epigenetic inhibition of BMP2 endocytosis. Am J Physiol Cell Physiol 283, C235-243, doi:10.1152/ajpcell.00234.2001 (2002).
  8. Farge, E. Mechanical induction of Twist in the Drosophila foregut/stomodeal primordium. Curr Biol 13, 1365-1377 (2003).
  9. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677-689, doi:10.1016/j.cell.2006.06.044 (2006).
  10. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6, 483-495 (2004).
  11. Desprat, N., Supatto, W., Pouille, P.-A., Beaurepaire, E. & Farge, E. Tissue deformation modulates twist expression to determine anterior midgut differentiation in Drosophila embryos. Developmental Cell 15, 470-477, doi:10.1016/j.devcel.2008.07.009 (2008).
  12. Brunet, T. et al. Evolutionary conservation of early mesoderm specification by mechanotransduction in Bilateria. Nature communications 4, doi:10.1038/ncomms3821 (2013).