The Mechanics and Genetics of Embryonic and Tumour Development team studies the role of mechanical strain and deformation of macroscopic biological structures at the cell or multi-cellular level, into the regulation and the generation of active biochemical processes at the microscopic molecular level, including gene expression, in vivo. The group focuses on the coupling between mechanical strains and biochemical signalling in developmental and cancer biology.
Our findings chronologically goes from the mechanical modulation of the endocytosis of signalling proteins as a mechanotransductive underlying molecular mechanism of cell trans-differentiation (early 2000’s), to its role in the involvement of mechanical cues in the trigger of early Drosophila embryos mesoderm invagination (late 2000’s). It additionally goes from our finding of the mechanosenstivity of the beta-catenin pathway as involved in the mechanical induction of early Drosophila embryos endoderm differentiation (from early to late 2000’s), most recently found as at the probable evolutionary origins of mesoderm emergence in the common ancestor of bilaterians, a process anomalously reactivated as a tumorigenic signal in compressed healthy epithelial tissues in response to tumour growth pressure in vivo (2010’s). From latest to earliest research:
Tumourigenesis: mechanical induction of tumourigenesis in compressed healthy cells, in response to the mechanical strains developed by tumorous growing tissues
We found β-catenin dependent mechanical induction of oncogenes expression and tumour initiation in both pre-tumorous and wild type mice colon healthy epithelia, in response to tumour growth pressure in vivo (M-E Fernandez-Sanchez, S. Barbier et al, Nature 2015, – Figure 1).
To do so, we mimicked the 1kPa tumour growth pressure in vivo by magnetically loading the mesenchemial conjunctive tissue with ultra-magnetic liposomes, which we submitted to a permanent magnetic field gradient due to a millimetric magnet sub-cutaneoulsy localized in front of the colon. Such mechanical strain activated the phosphorylation of both the Y654-beta-catenin leading to the release of a junctional pool into the cytoplasm. It additionally led to the phosphorylation of Ser9-GSK3b allowing the nuclear translocation of the cytoplasmic beta-catenin into the nucleus and the expression of its tumorigenic target genes. The same responses are observed in the non-tumorous crypts compressed by neighbouring Notch-hyperproliferative crypts of a mice model of tumour progression.
Evo-Devo: a mechano-transductive origin of mesoderm emergence in the common ancestor of bilaterian complex animals
We found that the mechanical activation of the beta-catenin pathway, anomalously activated in the process of tumour development, is an ancestral property, having been probably involved in the emergence of first differentiation patterns in ancient organism embryos, such as in the evolutionary emergence of the mesoderm in the last common ancestor of bilaterians. We effectively demonstrated the conservation of mechanical induction as involved in early mesoderm differentiation in both the zebrafish and Drosophila embryo, initiated by the mechanotransductive phosphorylation of the Y654 site of beta-catenin impairing its interaction with E-cadherins, leading to its release from the junctions to the cytoplasm and nuclei, and subsequently to the brackury and twist earliest mesoderm target genes expression, respectively (Figure 2).
The evolutionary origin of mesoderm emergence remains a major persisting opened question of Evo-Devo. Our results allow to suggest mechanostransductive Y654 phosphorylation in response to first embryonic morphogenetic movements at the origin of mesoderm emergence in the 570 millions years ago last common ancestor of bilaterians (Bouclet, Brunet et al, Nature Comm. 2013).
Developmental Biology: mechano-genetic and mechano-proteic reciprocal coupling in the regulation of gastrulating embryos development
Embryonic development is a coordination of multi-cellular biochemical patterning and morphogenetic movements. Last decades revealed the close control of Myosin-II dependent biomechanical morphogenesis by patterning gene expression, with constant progress in the understanding of the underlying molecular mechanisms. We recently revealed reversed control of the Twist developmental differentiation patterning gene expression (Figure 3) and of Myosin-II active relocalisation (Figure 4) by the mechanical strains developed by morphogenetic movements at Drosophila gastrulation, through mechanotransduction processes involving the Armadillo/beta-catenin and the down-stream of Fog signalling pathways (due mechanical inhibition of Fog endocytosis in this case, see next paragraph), respectively.
We used experimental tools (genetic and biophysical control of morphogenetic movements, Figure 3), and theoretical tools (simulations integrating the accumulated knowledge in the genetics of early embryonic development and morphogenesis) (Figure 5), to uncouple genetic inputs from mechanical inputs in the regulation of Twist meso-endoderm gene expression and Myosin-II active relocalisation. Specifically, we set-up an innovative magnetic tweezers tool to measure and apply physiological strains and forces in vivo, allowing to mimic morphogenetic movements from the inside of the tissue in living embryos (Figure 3). Farge, Curr. Biol., 2003; Desprat et al, Dev Cell, 2008; Pouille et al Phys. Biol. 2008; Ahmadi, Pouille et al, Science Signalling, 2009).
Endocytosis: vesicle budding driving force; mechanical modulation of endocytosis as a mechanotransduction process triggering transdifferentiation
Historically, the first main thematic studied in the team was the motor role of biological membrane soft matter elasticity into the budding driving force of vesiculation initiating plasma membrane endocytosis (Rauch et al, Bioph. J, 2000), as well as the role of mechanical inhibition of morphogene endocytosis in mechanical induction of cell transdifferentiation (Figure 6, Rauch et al, Am. J. Cell Phys, 2002).