TY - JOUR
T1 - Phenotypic plasticity and cell fate decisions in cancer
T2 - Insights from dynamical systems theory
AU - Jia, Dongya
AU - Jolly, Mohit Kumar
AU - Kulkarni, Prakash
AU - Levine, Herbert
N1 - Funding Information:
We would like to thank Xuefei Li (Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA) and Min-Yeh Tsai (Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA) for a critical reading and helpful discussion of the manuscript. Herbert Levine was supported by the Physics Frontiers Center National Science Foundation (NSF) grant PHY-1427654 and the NSF grants DMS-1361411 and PHY-1605817. Herbert Levine was also supported by the Cancer Prevention and Research Institute of Texas (CPRIT) grants R1111. Mohit Kumar Jolly has a training fellowship from the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (CPRIT Grant RP170593). Prakash Kulkarni would like to dedicate this article to Prof. Vidyanand Nanjundiah on the occasion of his 70th birthday.
Publisher Copyright:
© 2017 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2017/7
Y1 - 2017/7
N2 - Waddington’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.
AB - Waddington’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.
KW - Cancer attractors
KW - Cell fate decision
KW - EMT
KW - Gene network dynamics
KW - Intrinsically disordered proteins
KW - Therapy resistance
UR - http://www.scopus.com/inward/record.url?scp=85021984910&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021984910&partnerID=8YFLogxK
U2 - 10.3390/cancers9070070
DO - 10.3390/cancers9070070
M3 - Review article
C2 - 28640191
AN - SCOPUS:85021984910
VL - 9
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 7
M1 - 70
ER -