Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

doi:10.1016/j.stem.2018.11.011

Review

. 2019 Jan 3;24(1):65-78.

doi: 10.1016/j.stem.2018.11.011. Epub 2018 Dec 13.

Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

Piyush B Gupta¹, Ievgenia Pastushenko², Adam Skibinski³, Cedric Blanpain⁴, Charlotte Kuperwasser⁵

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: piyush@mit.edu.
² Université Libre de Bruxelles, Laboratory of Stem Cells and Cancer, Brussels 1070, Belgium.
³ Department of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington St., Boston, MA 02111, USA.
⁴ Université Libre de Bruxelles, Laboratory of Stem Cells and Cancer, Brussels 1070, Belgium; WELBIO, Université Libre de Bruxelles, Brussels 1070, Belgium. Electronic address: cedric.blanpain@ulb.ac.be.
⁵ Université Libre de Bruxelles, Laboratory of Stem Cells and Cancer, Brussels 1070, Belgium; Department of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA. Electronic address: charlotte.kuperwasser@tufts.edu.

PMID: 30554963
PMCID: PMC7297507
DOI: 10.1016/j.stem.2018.11.011

Review

Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

Piyush B Gupta et al. Cell Stem Cell. 2019.

. 2019 Jan 3;24(1):65-78.

doi: 10.1016/j.stem.2018.11.011. Epub 2018 Dec 13.

Authors

Piyush B Gupta¹, Ievgenia Pastushenko², Adam Skibinski³, Cedric Blanpain⁴, Charlotte Kuperwasser⁵

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: piyush@mit.edu.
² Université Libre de Bruxelles, Laboratory of Stem Cells and Cancer, Brussels 1070, Belgium.
³ Department of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington St., Boston, MA 02111, USA.
⁴ Université Libre de Bruxelles, Laboratory of Stem Cells and Cancer, Brussels 1070, Belgium; WELBIO, Université Libre de Bruxelles, Brussels 1070, Belgium. Electronic address: cedric.blanpain@ulb.ac.be.
⁵ Université Libre de Bruxelles, Laboratory of Stem Cells and Cancer, Brussels 1070, Belgium; Department of Developmental, Chemical and Molecular Biology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA; Raymond and Beverly Sackler Convergence Laboratory, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA. Electronic address: charlotte.kuperwasser@tufts.edu.

PMID: 30554963
PMCID: PMC7297507
DOI: 10.1016/j.stem.2018.11.011

Abstract

Our traditional understanding of phenotypic plasticity in adult somatic cells comprises dedifferentiation and transdifferentiation in the context of tissue regeneration or wound healing. Although dedifferentiation is central to tissue repair and stemness, this process inherently carries the risk of cancer initiation. Consequently, recent research suggests phenotypic plasticity as a new paradigm for understanding cancer initiation, progression, and resistance to therapy. Here, we discuss how cells acquire plasticity and the role of plasticity in initiating cancer, cancer progression, and metastasis and in developing therapy resistance. We also highlight the epithelial-to-mesenchymal transition (EMT) and known molecular mechanisms underlying plasticity and we consider potential therapeutic avenues.

Keywords: cancer; epithelial to mesenchymal transition; plasticity; therapy resistance.

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Figures

**Figure 1.. Types of Differentiation that Are Induced during Cellular Plasticity.**
Types of epithelial differentiation and plasticity seen in the mammary gland and how it relates to more primitive states of multipotency seen during embryonic development.

**Figure 2.. Tumor Transition States Occurring during EMT.**
(A–D) Changes in cell morphology (A), gene expression (B), chromatin remodeling (C), and transcription factors (D) involved in the regulation of different tumor transition states occurring during EMT.

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References

1. Aceto N1, Toner M2, Maheswaran S3, Haber DA4. En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition. (2015) Trends Cancer 1(1):44–52. - PubMed
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1. Beck B, Lapouge G, Rorive S, Drogat B, Desaedelaere K, Delafaille S, Dubois C, Salmon I, Willekens K, Marine JC, Blanpain C.Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. (2015) Cell Stem Cell 16(1):67–79. - PubMed
1. Bedogni et al., 2008

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[1] Aceto N1, Toner M2, Maheswaran S3, Haber DA4. En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition. (2015) Trends Cancer 1(1):44–52. - PubMed

[2] Aceto N1, Toner M2, Maheswaran S3, Haber DA4. En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition. (2015) Trends Cancer 1(1):44–52. - PubMed

[3] Arienti et al., 2013b;

[4] Arienti et al., 2013b;

[5] Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, and Kasimir-Bauer S (2009). Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Research 11, - PMC - PubMed

[6] Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, and Kasimir-Bauer S (2009). Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Research 11, - PMC - PubMed

[7] Beck B, Lapouge G, Rorive S, Drogat B, Desaedelaere K, Delafaille S, Dubois C, Salmon I, Willekens K, Marine JC, Blanpain C.Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. (2015) Cell Stem Cell 16(1):67–79. - PubMed

[8] Beck B, Lapouge G, Rorive S, Drogat B, Desaedelaere K, Delafaille S, Dubois C, Salmon I, Willekens K, Marine JC, Blanpain C.Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. (2015) Cell Stem Cell 16(1):67–79. - PubMed

[9] Bedogni et al., 2008

[10] Bedogni et al., 2008

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Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

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Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

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