Mechanics of development and disease


Vito Conte | Junior Group Leader
Agata Nyga | Postdoctoral Researcher

About

In the group we advance cross-disciplinary research at the interface between engineering, biology and physics. We are interested in deciphering the physical mechanisms of development and disease in biological organisms.

We do so by studying how cell and tissue mechanics determine structure and function in these organisms. To that end, we are developing new biophysical tools to compute cell and tissue forces in arbitrary 3D environments that have realistic geometries and material properties, such as anisotropy, heterogeneity, poroelasticity, and non-linear viscoelasticity. We utilise these tools to carry out in vivo and in vitro mechanical measurements, which we integrate into 2D and 3D physical models of the biological organisms under study. The in silico models we build allow us to make predictive biomechanical analyses of these organisms by studying the necessary and sufficient conditions for their development and disease under conditions very close to the real ones.

The group currently has two main fields of research inside IBEC’s Bioengineering for Future Medicine pillar.

Biomechanical regulation of cancer progression
Our research in this field moves from growing evidence that cancer progression alters mechanical properties of cells and tissues affected by the disease. However, we ignore whether these alterations feed back into the cancer progression and, for that reason, may represent potential means to hinder or arrest the disease biomechanically. We want to understand the interplay between mechanics and malignancy of tissues to help identify new biomechanical markers or physical mechanisms of cancer progression that are clinically targetable for the prevention and treatment of the disease.

Embryo morphogenesis
In 2016 we started to explore how cell and tissue mechanics in the early embryo are associated to and regulated by a concerted programme of gene expression. This programme transforms the embryo from a simple unstructured organism into a healthy complex organism. Specifically, we’re interested in quantifying the forces defining the physical mechanisms that morph the fruit fly blastula into the gastrula. Gastrulation is a key stage in the healthy development of the embryo of most animals: if anything goes awry during this process a diseased or abormal phenotype is produced if the embryo survives at all.

Right: In vivo biomechanical quantification of ventral furrow invagination in the Drosophila melanogaster embryo.

News/Jobs

IBEC at the forefront of research in mechanobiology
20/06/2017

Three IBEC group leaders – Pere Roca-Cusachs, Vito Conte and Xavier Trepat – consolidate the institute’s leadership in mechanobiology by publishing a review of the field in Nature Cell Biology.


IBEC’s newest junior group leader: Vito Conte
15/02/2016

Vito Conte may be familiar to many, having spent more than four years in Xavier Trepat’s Integrative Cell and Tissue Dynamics group, first as a postdoc and later as a Juan de la Cierva fellow. Vito now is a Ramon y Cajal fellow and leads the Mechanics of Development and Disease group, which will take a new direction as he develops new biophysical tools to quantify the mechanics of cell and tissues in 3D environments.


Projects

National projects
CancerMechReg Regulacion biomecanica de la progresion del cancer (2016-2019) MINECO, Proyectos I+D Excelencia Vito Conte

Publications


Roca-Cusachs, Pere, Conte, Vito, Trepat, Xavier, (2017). Quantifying forces in cell biology Nature Cell Biology 19, (7), 742-751

Cells exert, sense, and respond to physical forces through an astounding diversity of mechanisms. Here we review recently developed tools to quantify the forces generated by cells. We first review technologies based on sensors of known or assumed mechanical properties, and discuss their applicability and limitations. We then proceed to draw an analogy between these human-made sensors and force sensing in the cell. As mechanics is increasingly revealed to play a fundamental role in cell function we envisage that tools to quantify physical forces may soon become widely applied in life-sciences laboratories.


Rodriguez-Franco, P., Brugués, A., Marin-Llaurado, A., Conte, V., Solanas, G., Batlle, E., Fredberg, J. J., Roca-Cusachs, P., Sunyer, R., Trepat, X., (2017). Long-lived force patterns and deformation waves at repulsive epithelial boundaries Nature Materials 16, (10), 1029-1036

For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries are commonly attributed to mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical events. Following contact between two epithelial monolayers expressing, respectively, EphB2 and its ligand ephrinB1, both monolayers exhibit oscillatory patterns of traction forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. With time, monolayers jam, accompanied by the emergence of deformation waves that propagate away from the boundary. This phenomenon is not specific to EphB2/ephrinB1 repulsion but is also present during the formation of boundaries with an inert interface and during fusion of homotypic epithelial layers. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary.

Keywords: Biological physics, Cellular motility


Perez-Mockus, Gantas, Mazouni, Khalil, Roca, Vanessa, Corradi, Giulia, Conte, Vito, Schweisguth, François, (2017). Spatial regulation of contractility by Neuralized and Bearded during furrow invagination in Drosophila Nature Communications 8, (1), 1594

Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralized (Neur), an E3 ubiquitin ligase active in the mesoderm, regulates collective apical constriction and furrow formation. Conversely, the Bearded (Brd) proteins antagonize maternal Neur and lower medial–apical contractility in the ectoderm: in Brd-mutant embryos, the ventral furrow invaginates properly but rapidly unfolds as medial MyoII levels increase in the ectoderm. Increasing contractility in the ectoderm via activated Rho similarly triggers furrow unfolding whereas decreasing contractility restores furrow invagination in Brd-mutant embryos. Thus, the inhibition of Neur by Brd in the ectoderm differentiates the mechanics of the ectoderm from that of the mesoderm and patterns the activity of MyoII along the dorsal–ventral axis.

Keywords: Drosophila, Gastrulation, Morphogenesis


Sunyer, R., Conte, V., Escribano, J., Elosegui-Artola, A., Labernadie, A., Valon, L., Navajas, D., García-Aznar, J. M., Muñoz, J. J., Roca-Cusachs, P., Trepat, X., (2016). Collective cell durotaxis emerges from long-range intercellular force transmission Science 353, (6304), 1157-1161

The ability of cells to follow gradients of extracellular matrix stiffness-durotaxis-has been implicated in development, fibrosis, and cancer. Here, we found multicellular clusters that exhibited durotaxis even if isolated constituent cells did not. This emergent mode of directed collective cell migration applied to a variety of epithelial cell types, required the action of myosin motors, and originated from supracellular transmission of contractile physical forces. To explain the observed phenomenology, we developed a generalized clutch model in which local stick-slip dynamics of cell-matrix adhesions was integrated to the tissue level through cell-cell junctions. Collective durotaxis is far more efficient than single-cell durotaxis; it thus emerges as a robust mechanism to direct cell migration during development, wound healing, and collective cancer cell invasion.



Equipment

  • Mechanical quantification in vitro and in vivo
  • Experimental physical modelling in silico

Collaborations

  • José Muñoz
    Polytechnic University of Catalonia (UPC)

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