Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

By M. Jolly, Marcelo Boareto, Bin Huang, D. Jia, Mingyang Lu, E. Ben-Jacob, José N. Onuchic, Herbert Levine. Frontiers in Oncology, 2015

662 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/07de4acb8d7a16fb1ec077758671b2a06a51c52a

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The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. Yibin Kang
2. K. Yeung
3. Jing Yang

In Molecular Biology

1. K. Yeung
2. Jing Yang
3. Wei Dang Lu
4. Yibin Kang
5. Yuhe Huang
6. Xiawei Wei
7. Weiqi Hong
8. R. Weinberg

In Oncology

1. K. Yeung
2. Yibin Kang
3. D. Bar-Sagi
4. Wei Dang Lu
5. Yuhe Huang
6. Jing Yang
7. Xiawei Wei
8. Weiqi Hong

Citations in the corpus

• Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “According to this hypothesis, the highest degree of plasticity and the highest potential to become stem cells are manifested in cells of intermediate EMT states that possess both epithelial and mesenchymal traits (Jolly et al., 2015; Nieto et al., 2016).”
• EMT subtype influences epithelial plasticity and mode of cell migration (2018, background): “Recent work has called attention to the fact that EMT can also exist along a spectrum, resulting in a bi-phenotypic partial EMT state wherein tumor cells retain both epithelial and mesenchymal programs; importantly, such a hybrid state has been proposed to confer a greater ability to metastasize tha”
• Epithelial–mesenchymal transition in tumor metastasis (2016, background): “In particular, the reversible EMT hypothesis suggests that partial, rather than complete, EMT states are more likely to associate with higher aggressiveness, plasticity, and tumor-initiating properties (Jolly et al., 2015).”
• The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis (2022, background): “Circulating tumor cells represent a heterogeneous group, and the various hybrid phenotypes of EMT from the epithelium (E) to mesenchyme (M) play significant roles in tumor heterogeneity [13, 199].”