Turn up apical actomyosin contractility and the model produces
epithelial invagination [17]. This study did not attempt to model
dynamics, or transitions of epithelia into individual cells, or cell
motility, or transitions between migratory modes. Modeling of
such transitions would therefore be an interesting future goal for
physicists and mechanical engineers interested in biology, in order
to continue to test how well this conceptual framework explains
diverse cell morphologies and behaviors.
Are these mechanical properties actually modular? That is, can
they be altered independently of one another? Mostly yes. The
families of molecules that endow cells with these properties are
known. Cell adhesion molecules such as classical cadherins provide
cell-cell cohesion, which can be tuned by expression levels and/or
post-translational modifications. Integrins are the dominant cellmatrix adhesion receptors, and it has long been known that an
intermediate level of cell-matrix adhesion is optimal for fibroblasts
to migrate [18]. Too little adhesion and cells slip, like trying to walk
on ice; too much and they stick. Actomyosin endows cells with
contractility, and this property is primarily tuned by levels and localization of Rho GTPase activity. Moreover, high Rho/myosin activity
is sufficient to convert a variety of individual cells and cell clusters
from mesenchymal to amoeboid migration modes [19–21]. This
applies to tumor cells and normal cells, in vitro and in vivo. Actin
polymerization is the main generator of protrusive force, usually
downstream of the GTPases Rac and Cdc42. Increasing Rac activity
converts cells from amoeboid to mesenchymal motility. Therefore
these four mechanical properties can be tuned independently, leading
to transitions in shape and behavior. Encouragingly, others have
converged onto similar ideas [14, 22, 23].
Though admittedly not as simple as the original EMT hypothesis, this framework of a cellular “phase space” is useful because it
synthesizes numerous, disparate observations into a unified concept. Like learning that the earth is not the center of the solar
system, and that there are many solar systems and galaxies, sometimes a deeper understanding requires recognition of greater complexity. Nevertheless, recognizing that simple, modular
components can build diverse and complex forms is an enticingly
powerful idea.
References
1. Thiery JP et al (2009) Epithelial-mesenchymal
transitions in development and disease. Cell
139:871–890
2. Lim J, Thiery JP (2012) Epithelialmesenchymal transitions: insights from development. Development 139:3471–3486
3. Lambert AW et al (2017) Emerging biological
principles of metastasis. Cell 168:670–691
4. Nieto MA et al (2016) EMT: 2016. Cell
166:21–45
5. Friedl P, Gilmour D (2009) Collective cell
migration in morphogenesis, regeneration and
cancer. Nat Rev Mol Cell Biol 10:445–457
6. Derynck R, Weinberg RA (2019) EMT and
cancer: more than meets the eye. Dev Cell
49:313–316
EMT, One of Many Morphological Transitions in Cellular Phase Space
17
epithelial invagination [17]. This study did not attempt to model
dynamics, or transitions of epithelia into individual cells, or cell
motility, or transitions between migratory modes. Modeling of
such transitions would therefore be an interesting future goal for
physicists and mechanical engineers interested in biology, in order
to continue to test how well this conceptual framework explains
diverse cell morphologies and behaviors.
Are these mechanical properties actually modular? That is, can
they be altered independently of one another? Mostly yes. The
families of molecules that endow cells with these properties are
known. Cell adhesion molecules such as classical cadherins provide
cell-cell cohesion, which can be tuned by expression levels and/or
post-translational modifications. Integrins are the dominant cellmatrix adhesion receptors, and it has long been known that an
intermediate level of cell-matrix adhesion is optimal for fibroblasts
to migrate [18]. Too little adhesion and cells slip, like trying to walk
on ice; too much and they stick. Actomyosin endows cells with
contractility, and this property is primarily tuned by levels and localization of Rho GTPase activity. Moreover, high Rho/myosin activity
is sufficient to convert a variety of individual cells and cell clusters
from mesenchymal to amoeboid migration modes [19–21]. This
applies to tumor cells and normal cells, in vitro and in vivo. Actin
polymerization is the main generator of protrusive force, usually
downstream of the GTPases Rac and Cdc42. Increasing Rac activity
converts cells from amoeboid to mesenchymal motility. Therefore
these four mechanical properties can be tuned independently, leading
to transitions in shape and behavior. Encouragingly, others have
converged onto similar ideas [14, 22, 23].
Though admittedly not as simple as the original EMT hypothesis, this framework of a cellular “phase space” is useful because it
synthesizes numerous, disparate observations into a unified concept. Like learning that the earth is not the center of the solar
system, and that there are many solar systems and galaxies, sometimes a deeper understanding requires recognition of greater complexity. Nevertheless, recognizing that simple, modular
components can build diverse and complex forms is an enticingly
powerful idea.
References
1. Thiery JP et al (2009) Epithelial-mesenchymal
transitions in development and disease. Cell
139:871–890
2. Lim J, Thiery JP (2012) Epithelialmesenchymal transitions: insights from development. Development 139:3471–3486
3. Lambert AW et al (2017) Emerging biological
principles of metastasis. Cell 168:670–691
4. Nieto MA et al (2016) EMT: 2016. Cell
166:21–45
5. Friedl P, Gilmour D (2009) Collective cell
migration in morphogenesis, regeneration and
cancer. Nat Rev Mol Cell Biol 10:445–457
6. Derynck R, Weinberg RA (2019) EMT and
cancer: more than meets the eye. Dev Cell
49:313–316
EMT, One of Many Morphological Transitions in Cellular Phase Space
17