Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory

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dc.citation.articleNumber70en_US
dc.citation.issueNumber7en_US
dc.citation.journalTitleCancersen_US
dc.citation.volumeNumber9en_US
dc.contributor.authorJia, Dongyaen_US
dc.contributor.authorJolly, Mohit Kumaren_US
dc.contributor.authorKulkarni, Prakashen_US
dc.contributor.authorLevine, Herberten_US
dc.date.accessioned2017-08-09T17:13:27Zen_US
dc.date.available2017-08-09T17:13:27Zen_US
dc.date.issued2017en_US
dc.description.abstractWaddington’s epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of “landscape” in the context of dynamical systems theory represents a high-dimensional space, in which each cell phenotype is considered as an “attractor” that is determined by interactions between multiple molecular players, and is buffered against environmental fluctuations. In addition, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss the phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of “cancer attractors”—hidden stable states of the underlying regulatory network that are not occupied by normal cells. Phenotypic transitions in cancer occur at varying levels depending on the context. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of therapy resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to therapies such as chemotherapy and androgen-deprivation therapy. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes “recanalization”, i.e., the exit from “cancer attractors” and re-entry into “normal attractors”, is more likely to succeed rather than a conventional approach that targets individual molecules/pathways.en_US
dc.identifier.citationJia, Dongya, Jolly, Mohit Kumar, Kulkarni, Prakash, et al.. "Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory." <i>Cancers,</i> 9, no. 7 (2017) MDPI: https://doi.org/10.3390/cancers9070070.en_US
dc.identifier.digitalPhenotypic_Plasticity_Cell_Fate_Decisionsen_US
dc.identifier.doihttps://doi.org/10.3390/cancers9070070en_US
dc.identifier.urihttps://hdl.handle.net/1911/96638en_US
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.rightsThis is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordEMTen_US
dc.subject.keywordcancer attractorsen_US
dc.subject.keywordcell fate decisionen_US
dc.subject.keywordgene network dynamicsen_US
dc.subject.keywordintrinsically disordered proteinsen_US
dc.subject.keywordtherapy resistanceen_US
dc.titlePhenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theoryen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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