meeting held in Kumamoto in November 2019 showed improved
animal models, which should be of tremendous help on this matter.
Importantly, the models should also be able to reproduce the
timing of events, not only to be able to more accurately follow the
progression to the metastatic disease but also to prevent misleading
interpretations. For instance, in animal models, the silencing of
EMT-TFs is usually performed from the very early stages of tumorigenesis and tumor progression. Under these experimental conditions, the lack of these EMT regulators leads to a well-documented
decrease in metastatic burden. This is usually interpreted as a
requirement of EMT for metastasis formation, and suggests that
inhibiting EMT should be beneficial in the clinic. However, the
most likely explanation in the aforementioned experimental setting
is that the decrease in metastatic burden results from a much lower
degree of invasion and dissemination. It is worth noting here that
the situation is very different in the clinical setting, as the vast
majority of cancer patients are diagnosed at the time when dissemination has already occurred. As it is accepted that disseminated
cancer cells need to revert towards a more epithelial phenotype
for metastatic colonization (see above), a strategy aimed at inhibiting EMT under these conditions could be counterproductive, as it
may promote colonization of already disseminated cancer cells.
Thus, a note of caution is essential when extrapolating from data
obtained in animal models, and this is important because it may
have a direct impact on the decision of therapeutic strategies.
Another source of putative misleading conclusions is due to
(1) the focal nature of the EMT and (2) the low level of expression
of the EMT-TFs. These two factors may affect the results and
interpretations of whole genome transcriptome analyses, preventing the detection of an EMT program. The limited areas of EMT
within a tumor may be diluted in bulk RNA sequencing. Although
this should not be a problem in single cell RNA sequencing
(scRNAseq) experiments, the low expression levels of EMT-TFs
may as well prevent their detection in scRNAseq studies.
6 The Benefits
Are you still afraid of the EMT? Think of it in a conceptual manner,
integrate it into the biology of the system and consider that the
progress in our knowledge of the molecular and cellular properties
of the different EMT programs together with the emergence of
commonalities should prove very useful in the design of optimized
animal models. This is all for the benefit of knowledge and essentially, for the opportunity to design better therapeutic strategies for
the benefit of the patients. Cancer and degenerative organ diseases
26
M. Angela Nieto
animal models, which should be of tremendous help on this matter.
Importantly, the models should also be able to reproduce the
timing of events, not only to be able to more accurately follow the
progression to the metastatic disease but also to prevent misleading
interpretations. For instance, in animal models, the silencing of
EMT-TFs is usually performed from the very early stages of tumorigenesis and tumor progression. Under these experimental conditions, the lack of these EMT regulators leads to a well-documented
decrease in metastatic burden. This is usually interpreted as a
requirement of EMT for metastasis formation, and suggests that
inhibiting EMT should be beneficial in the clinic. However, the
most likely explanation in the aforementioned experimental setting
is that the decrease in metastatic burden results from a much lower
degree of invasion and dissemination. It is worth noting here that
the situation is very different in the clinical setting, as the vast
majority of cancer patients are diagnosed at the time when dissemination has already occurred. As it is accepted that disseminated
cancer cells need to revert towards a more epithelial phenotype
for metastatic colonization (see above), a strategy aimed at inhibiting EMT under these conditions could be counterproductive, as it
may promote colonization of already disseminated cancer cells.
Thus, a note of caution is essential when extrapolating from data
obtained in animal models, and this is important because it may
have a direct impact on the decision of therapeutic strategies.
Another source of putative misleading conclusions is due to
(1) the focal nature of the EMT and (2) the low level of expression
of the EMT-TFs. These two factors may affect the results and
interpretations of whole genome transcriptome analyses, preventing the detection of an EMT program. The limited areas of EMT
within a tumor may be diluted in bulk RNA sequencing. Although
this should not be a problem in single cell RNA sequencing
(scRNAseq) experiments, the low expression levels of EMT-TFs
may as well prevent their detection in scRNAseq studies.
6 The Benefits
Are you still afraid of the EMT? Think of it in a conceptual manner,
integrate it into the biology of the system and consider that the
progress in our knowledge of the molecular and cellular properties
of the different EMT programs together with the emergence of
commonalities should prove very useful in the design of optimized
animal models. This is all for the benefit of knowledge and essentially, for the opportunity to design better therapeutic strategies for
the benefit of the patients. Cancer and degenerative organ diseases
26
M. Angela Nieto