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Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis.

Jolly MK, Boareto M, Huang B, Jia D, Lu M, Ben-Jacob E, Onuchic JN, Levine H - Front Oncol (2015)

Bottom Line: Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell-cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs.These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype.Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University , Houston, TX , USA ; Department of Bioengineering, Rice University , Houston, TX , USA.

ABSTRACT
Transitions between epithelial and mesenchymal phenotypes - the epithelial to -mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) - are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a "three-way" switch giving rise to three distinct phenotypes - E, M and hybrid E/M - and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell-cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary "bad actors" of metastasis.

No MeSH data available.


Related in: MedlinePlus

Cell–cell communication and partial EMT. (A) Coupling of EMT circuit with Notch circuit. Notch pathway, when activated by Jagged or Delta, belonging to neighboring cell, can activate Jagged and Notch, but inhibit Delta. EMT circuit couples with Notch circuit in many ways – miR-200 inhibits Jagged1, miR-34 inhibits both Notch and Delta, and NICD can activate SNAIL to drive EMT. (B) Notch-Delta signaling between two cells induces opposite fates in them – one cell behaves as a Sender (high Delta, low Notch) and the other a Receiver (high Notch, low Delta). Due to this lateral inhibition, it can promote “salt-and-pepper” based patterns. (C) Notch-Jagged signaling between two cells induces similar fates in them – lateral induction – and thus leads to patterns with all cells with the same fate. (D) (Left) cells in a partial EMT and interacting via N-D signaling might not be spatially close to each other, because N-D signaling inhibits two neighbors to adopt the same fate. (right) Cells in a partial EMT and interacting via N-J signaling can mutually stabilize the E/M phenotype and stay together as a cluster. Figure adapted from Ref. (173).
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Figure 8: Cell–cell communication and partial EMT. (A) Coupling of EMT circuit with Notch circuit. Notch pathway, when activated by Jagged or Delta, belonging to neighboring cell, can activate Jagged and Notch, but inhibit Delta. EMT circuit couples with Notch circuit in many ways – miR-200 inhibits Jagged1, miR-34 inhibits both Notch and Delta, and NICD can activate SNAIL to drive EMT. (B) Notch-Delta signaling between two cells induces opposite fates in them – one cell behaves as a Sender (high Delta, low Notch) and the other a Receiver (high Notch, low Delta). Due to this lateral inhibition, it can promote “salt-and-pepper” based patterns. (C) Notch-Jagged signaling between two cells induces similar fates in them – lateral induction – and thus leads to patterns with all cells with the same fate. (D) (Left) cells in a partial EMT and interacting via N-D signaling might not be spatially close to each other, because N-D signaling inhibits two neighbors to adopt the same fate. (right) Cells in a partial EMT and interacting via N-J signaling can mutually stabilize the E/M phenotype and stay together as a cluster. Figure adapted from Ref. (173).

Mentions: Importantly, Notch-Jagged (N-J) communication might be the preferred mode of tumor–stroma signaling than Notch-Delta (N-D) signaling due to its multiple potential synergistic effects in the tumor ecology. Two cells interacting via N-D signaling usually adopt distinct fates – one cell behaves as Sender [high ligand (Delta), low receptor (Notch)] and the other as Receiver [low ligand (Delta), high receptor (Notch)], therefore allowing only one-directional signaling and “salt-and-pepper” cell-fate patterns (178) (Figure 8B). Conversely, the two cells interacting via N-J signaling can adopt similar fates – hybrid Sender/Receiver [medium ligand (Jagged), medium receptor (Notch)] that enables bidirectional communication between them (172, 173), and allows lateral induction, i.e., a cell induces its neighbor to adopt the same fate as that of its own (179–181) (Figure 8C). Due to this lateral induction mechanism observed in N-J signaling, a cluster of E/M cells interacting via N-J signaling might mutually stabilize their “metastable” phenotype and consequently maintain high “stemness” (172). This notion is supported by the involvement of Notch signaling in wound healing (182). N-J signaling in collectively moving cells can induce or maintain similar fates as that of the neighboring cells, thereby coordinating wound healing, but excessive N-D signaling might impair it. Importantly, if partial EMT is defined as (high miR-200, low ZEB) rather than (medium miR-200, medium ZEB), collectively moving cells with active Notch signaling are likely to have suppressed N-J signaling almost completely because miR-200 inhibits Jagged1 strongly (183) and therefore might diversify their fates via N-D signaling, a phenomenon that would impair wound healing (41) (Figures 8A,D). A tantalizing possibility nevertheless, it remains to be tested both experimentally and via a theoretical model of the coupled core EMT circuit and Notch-Delta-Jagged signaling via interactions such as miR-200 inhibits Jagged (183), miR-34 inhibits Delta and Notch (184, 185), and NICD activates SNAIL (98, 186).


Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis.

Jolly MK, Boareto M, Huang B, Jia D, Lu M, Ben-Jacob E, Onuchic JN, Levine H - Front Oncol (2015)

Cell–cell communication and partial EMT. (A) Coupling of EMT circuit with Notch circuit. Notch pathway, when activated by Jagged or Delta, belonging to neighboring cell, can activate Jagged and Notch, but inhibit Delta. EMT circuit couples with Notch circuit in many ways – miR-200 inhibits Jagged1, miR-34 inhibits both Notch and Delta, and NICD can activate SNAIL to drive EMT. (B) Notch-Delta signaling between two cells induces opposite fates in them – one cell behaves as a Sender (high Delta, low Notch) and the other a Receiver (high Notch, low Delta). Due to this lateral inhibition, it can promote “salt-and-pepper” based patterns. (C) Notch-Jagged signaling between two cells induces similar fates in them – lateral induction – and thus leads to patterns with all cells with the same fate. (D) (Left) cells in a partial EMT and interacting via N-D signaling might not be spatially close to each other, because N-D signaling inhibits two neighbors to adopt the same fate. (right) Cells in a partial EMT and interacting via N-J signaling can mutually stabilize the E/M phenotype and stay together as a cluster. Figure adapted from Ref. (173).
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Figure 8: Cell–cell communication and partial EMT. (A) Coupling of EMT circuit with Notch circuit. Notch pathway, when activated by Jagged or Delta, belonging to neighboring cell, can activate Jagged and Notch, but inhibit Delta. EMT circuit couples with Notch circuit in many ways – miR-200 inhibits Jagged1, miR-34 inhibits both Notch and Delta, and NICD can activate SNAIL to drive EMT. (B) Notch-Delta signaling between two cells induces opposite fates in them – one cell behaves as a Sender (high Delta, low Notch) and the other a Receiver (high Notch, low Delta). Due to this lateral inhibition, it can promote “salt-and-pepper” based patterns. (C) Notch-Jagged signaling between two cells induces similar fates in them – lateral induction – and thus leads to patterns with all cells with the same fate. (D) (Left) cells in a partial EMT and interacting via N-D signaling might not be spatially close to each other, because N-D signaling inhibits two neighbors to adopt the same fate. (right) Cells in a partial EMT and interacting via N-J signaling can mutually stabilize the E/M phenotype and stay together as a cluster. Figure adapted from Ref. (173).
Mentions: Importantly, Notch-Jagged (N-J) communication might be the preferred mode of tumor–stroma signaling than Notch-Delta (N-D) signaling due to its multiple potential synergistic effects in the tumor ecology. Two cells interacting via N-D signaling usually adopt distinct fates – one cell behaves as Sender [high ligand (Delta), low receptor (Notch)] and the other as Receiver [low ligand (Delta), high receptor (Notch)], therefore allowing only one-directional signaling and “salt-and-pepper” cell-fate patterns (178) (Figure 8B). Conversely, the two cells interacting via N-J signaling can adopt similar fates – hybrid Sender/Receiver [medium ligand (Jagged), medium receptor (Notch)] that enables bidirectional communication between them (172, 173), and allows lateral induction, i.e., a cell induces its neighbor to adopt the same fate as that of its own (179–181) (Figure 8C). Due to this lateral induction mechanism observed in N-J signaling, a cluster of E/M cells interacting via N-J signaling might mutually stabilize their “metastable” phenotype and consequently maintain high “stemness” (172). This notion is supported by the involvement of Notch signaling in wound healing (182). N-J signaling in collectively moving cells can induce or maintain similar fates as that of the neighboring cells, thereby coordinating wound healing, but excessive N-D signaling might impair it. Importantly, if partial EMT is defined as (high miR-200, low ZEB) rather than (medium miR-200, medium ZEB), collectively moving cells with active Notch signaling are likely to have suppressed N-J signaling almost completely because miR-200 inhibits Jagged1 strongly (183) and therefore might diversify their fates via N-D signaling, a phenomenon that would impair wound healing (41) (Figures 8A,D). A tantalizing possibility nevertheless, it remains to be tested both experimentally and via a theoretical model of the coupled core EMT circuit and Notch-Delta-Jagged signaling via interactions such as miR-200 inhibits Jagged (183), miR-34 inhibits Delta and Notch (184, 185), and NICD activates SNAIL (98, 186).

Bottom Line: Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell-cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs.These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype.Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University , Houston, TX , USA ; Department of Bioengineering, Rice University , Houston, TX , USA.

ABSTRACT
Transitions between epithelial and mesenchymal phenotypes - the epithelial to -mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) - are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a "three-way" switch giving rise to three distinct phenotypes - E, M and hybrid E/M - and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell-cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary "bad actors" of metastasis.

No MeSH data available.


Related in: MedlinePlus