spatially organized in distinct patterns in different contexts. While
Notch-Delta signaling leads to a “salt-and-pepper” patterning
wherein hybrid E/M and mesenchymal cells are surrounded by
epithelial cells, Notch-Jagged signaling leads to the emergence of
clusters of these cell types. The spatial organization of epithelialmesenchymal heterogeneity is a distinguishing feature of this mechanism for emergence of heterogeneity. Neither cell-to-cell variation
in kinetic parameters governing EMT regulation nor random partitioning of molecules during cell division can lead to such behavior. Spatial heterogeneity in the abundance of different phenotypes
is a characteristic of tumors [74]. For example, mesenchymal cancer
stem cells are abundant near the tumor-stroma boundary while
cancer stem cells exhibiting a hybrid E/M phenotype tend to
localize in the interior of the tumor [75]. The cell–cell
communication-dependent mechanism for the generation of phenotypic heterogeneity described here can be used to understand
and describe such features of the tumor microenvironment [76].
7 Modeling the Coupling Between EMT and Stemness in Cancer Cells
Across cancer types, subpopulations of tumor cells that exhibit
stem-cell-like behavior, i.e., an increased capacity to repopulate
tumors, have been observed [77]. These cancer stem cells
(CSCs), often inherently resistant to anticancer therapies, can not
only repopulate the tumor post-therapy but also re-create the
intra-tumoral heterogeneity exhibited by the original tumor. The
connection between EMT and the appearance of stem-cell-like
properties in cancer cells has been studied for a long time. Initial
studies argued that tumor cells must undergo a complete EMT in
order to exhibit traits of CSCs [78, 79]. This proposition was
consistent with the then prevalent perception of EMT as a binary
process. Later studies showed that EMT/MET and cancer cell
stemness are both highly dynamic processes. Cancer cells can
exhibit hybrid E/M phenotypes and inter-convert between the
different EMT-associated phenotypes. Similarly, cancer cells can
switch between CSC and non-CSC phenotypic states, maintaining
a dynamic equilibrium in a population of cancer cells [80–83]. Due
to these developments, a more nuanced picture of the
EMT-stemness
connection
has
emerged
wherein
all
EMT-associated phenotypes—epithelial, mesenchymal, and hybrid
E/M—can exhibit stemness properties depending on the strength
of the coupling between the modules regulating EMT and
stemness.
In cancer cells, stemness is regulated by a 2-component
decision-making circuit (Fig. 8) wherein LIN28 and let-7, a
micro-RNA, form a mutual inhibitory loop. NF-κB activates the
expression of both LIN28 and let-7 and thus acts as an input to this
Mathematical Modelling of EMT
405
Notch-Delta signaling leads to a “salt-and-pepper” patterning
wherein hybrid E/M and mesenchymal cells are surrounded by
epithelial cells, Notch-Jagged signaling leads to the emergence of
clusters of these cell types. The spatial organization of epithelialmesenchymal heterogeneity is a distinguishing feature of this mechanism for emergence of heterogeneity. Neither cell-to-cell variation
in kinetic parameters governing EMT regulation nor random partitioning of molecules during cell division can lead to such behavior. Spatial heterogeneity in the abundance of different phenotypes
is a characteristic of tumors [74]. For example, mesenchymal cancer
stem cells are abundant near the tumor-stroma boundary while
cancer stem cells exhibiting a hybrid E/M phenotype tend to
localize in the interior of the tumor [75]. The cell–cell
communication-dependent mechanism for the generation of phenotypic heterogeneity described here can be used to understand
and describe such features of the tumor microenvironment [76].
7 Modeling the Coupling Between EMT and Stemness in Cancer Cells
Across cancer types, subpopulations of tumor cells that exhibit
stem-cell-like behavior, i.e., an increased capacity to repopulate
tumors, have been observed [77]. These cancer stem cells
(CSCs), often inherently resistant to anticancer therapies, can not
only repopulate the tumor post-therapy but also re-create the
intra-tumoral heterogeneity exhibited by the original tumor. The
connection between EMT and the appearance of stem-cell-like
properties in cancer cells has been studied for a long time. Initial
studies argued that tumor cells must undergo a complete EMT in
order to exhibit traits of CSCs [78, 79]. This proposition was
consistent with the then prevalent perception of EMT as a binary
process. Later studies showed that EMT/MET and cancer cell
stemness are both highly dynamic processes. Cancer cells can
exhibit hybrid E/M phenotypes and inter-convert between the
different EMT-associated phenotypes. Similarly, cancer cells can
switch between CSC and non-CSC phenotypic states, maintaining
a dynamic equilibrium in a population of cancer cells [80–83]. Due
to these developments, a more nuanced picture of the
EMT-stemness
connection
has
emerged
wherein
all
EMT-associated phenotypes—epithelial, mesenchymal, and hybrid
E/M—can exhibit stemness properties depending on the strength
of the coupling between the modules regulating EMT and
stemness.
In cancer cells, stemness is regulated by a 2-component
decision-making circuit (Fig. 8) wherein LIN28 and let-7, a
micro-RNA, form a mutual inhibitory loop. NF-κB activates the
expression of both LIN28 and let-7 and thus acts as an input to this
Mathematical Modelling of EMT
405