as the survival properties of cells that undergo EMT also make
them resistant to chemo- and radiotherapy [20].
2. Stemness. The EMT has been proposed to endow cells with
stem cell-like properties, which again is fundamental in the
embryo for cells to differentiate into different tissues once
they reach their destination. In cancer, disseminated cells
need to maintain the ability to form new tumors at distant
sites. Out of the three associated properties, survival, low proliferation, and stemness, the latter has been more difficult to
analyze and somehow also subjected to debate. After the seminal discovery of the relationship between EMT and stemness
[21, 22], the idea was that there was a correlation between the
mesenchymal phenotype and stemness, and this is not correct.
The general idea is that the full mesenchymal phenotype is
incompatible with stemness, in agreement with (1) embryonic
stem cells (ESCs) being epithelial, and (2) the requirement for
fibroblasts to undergo the EMT reverse process (MET) during
reprogramming to iPSCs [23, 24]. This is also compatible with
the finding the EMT-TFs are downregulated during colonization and metastasis formation [17, 25–28]. In summary, stemness is better manifested at intermediate states in the EMT
spectrum and is not a fixed property of cells, but rather relies
on cell plasticity. As such, EMT is important for delamination
and local invasion, but it is not sufficient for metastatic colonization, that requires a certain degree of reversibility towards a
more epithelial phenotype compatible with stemness. All this
explains why correlation between EMT and metastasis may be not
direct, as it is plasticity that really matters. See Ref. 29 for a
discussion on cell heterogeneity in EMT and stemness.
5 The Challenge: Designing and Interpreting Optimal Models
One of the big challenges in the EMT in cancer field is the design of
optimized animal models that can recapitulate the different steps of
tumor progression while allowing cell plasticity and behavior to be
followed throughout the metastatic cascade. Needless to say, and as
mentioned above, the models need to take into account the complexity of the process, and among other sources of heterogeneity,
the tissue-specific EMT programs. Thus, it is important to analyze
the experimental system for expression codes and phenotypic plasticity before designing the reporters and/or the players to target.
Better reporter systems that can simultaneously detect cell plasticity
and cell lineages should be very helpful, together with optimized
protocols to recover the full complement of circulating tumor cells
(CTCs). Fortunately, several reports presented at the IX TEMTIA
Are You Interested or Afraid of Working on EMT?
25
them resistant to chemo- and radiotherapy [20].
2. Stemness. The EMT has been proposed to endow cells with
stem cell-like properties, which again is fundamental in the
embryo for cells to differentiate into different tissues once
they reach their destination. In cancer, disseminated cells
need to maintain the ability to form new tumors at distant
sites. Out of the three associated properties, survival, low proliferation, and stemness, the latter has been more difficult to
analyze and somehow also subjected to debate. After the seminal discovery of the relationship between EMT and stemness
[21, 22], the idea was that there was a correlation between the
mesenchymal phenotype and stemness, and this is not correct.
The general idea is that the full mesenchymal phenotype is
incompatible with stemness, in agreement with (1) embryonic
stem cells (ESCs) being epithelial, and (2) the requirement for
fibroblasts to undergo the EMT reverse process (MET) during
reprogramming to iPSCs [23, 24]. This is also compatible with
the finding the EMT-TFs are downregulated during colonization and metastasis formation [17, 25–28]. In summary, stemness is better manifested at intermediate states in the EMT
spectrum and is not a fixed property of cells, but rather relies
on cell plasticity. As such, EMT is important for delamination
and local invasion, but it is not sufficient for metastatic colonization, that requires a certain degree of reversibility towards a
more epithelial phenotype compatible with stemness. All this
explains why correlation between EMT and metastasis may be not
direct, as it is plasticity that really matters. See Ref. 29 for a
discussion on cell heterogeneity in EMT and stemness.
5 The Challenge: Designing and Interpreting Optimal Models
One of the big challenges in the EMT in cancer field is the design of
optimized animal models that can recapitulate the different steps of
tumor progression while allowing cell plasticity and behavior to be
followed throughout the metastatic cascade. Needless to say, and as
mentioned above, the models need to take into account the complexity of the process, and among other sources of heterogeneity,
the tissue-specific EMT programs. Thus, it is important to analyze
the experimental system for expression codes and phenotypic plasticity before designing the reporters and/or the players to target.
Better reporter systems that can simultaneously detect cell plasticity
and cell lineages should be very helpful, together with optimized
protocols to recover the full complement of circulating tumor cells
(CTCs). Fortunately, several reports presented at the IX TEMTIA
Are You Interested or Afraid of Working on EMT?
25