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Cancer: More than a geneticist’s Pandora’s box

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Abstract

Despite identical genetic constitution, a cancer cell population can exhibit phenotypic variations termed as non-genetic/non-mutational heterogeneity. Such heterogeneity – a ubiquitous nature of biological systems – has been implicated in metastasis, therapy resistance and tumour relapse. Here, we review the evidence for existence, sources and implications of non-genetic heterogeneity in multiple cancer types. Stochasticity/noise in transcription, protein conformation and/or external microenvironment can underlie such heterogeneity. Moreover, the existence of multiple possible cell states (phenotypes) as a consequence of the emergent dynamics of gene regulatory networks may enable reversible cell-state transitions (phenotypic plasticity) that can facilitate adaptive drug resistance and higher metastatic fitness. Finally, we highlight how computational and mathematical models can drive a better understanding of non-genetic heterogeneity and how a systems-level approach integrating mathematical modeling and in vitro/in vivo experiments can map the diverse phenotypic repertoire and identify therapeutic vulnerabilities of an otherwise clonal cell population.

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References

  • Andriani F, Bertolini G, Facchinetti F, et al. 2016 Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells. Mol. Oncol. 10 253–271

    Article  CAS  PubMed  Google Scholar 

  • Agozzino L, Balázsi G, Wang J and Dill KA 2020 How do cells adapt? Stories told in landscapes. Annu. Rev. Chem. Biomol. Eng. 11 155–182

    Article  PubMed  PubMed Central  Google Scholar 

  • Asadullah A, Kumar S, Saxena N, et al. 2021 Combined heterogeneity in cell size and deformability promotes cancer invasiveness. J. Cell Sci. 134 jcs250225

    Article  CAS  PubMed  Google Scholar 

  • Bah A, Vernon RM, Siddiqui Z, et al. 2015 Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. Nature 519 106–109

    Article  CAS  PubMed  Google Scholar 

  • Balaban NQ, Merrin J, Chait R, Kowalik L and Leibler S 2004 Bacterial persistence as a phenotypic switch. Science 305 1622–1625

    Article  CAS  PubMed  Google Scholar 

  • Balázsi G, Van Oudenaarden A and Collins JJ 2011 Cellular decision making and biological noise: from microbes to mammals. Cell 144 910–925

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Barcellos-Hoff MH and Ravani SA 2000 Irradiated mammary gland stroma promotes the expression of tumourigenic potential by unirradiated epithelial cells. Cancer Res. 60 1254–1260

    CAS  PubMed  Google Scholar 

  • Barclay WW, Woodruff RD, Hall MC and Cramer SD 2005 A system for studying epithelial-stromal interactions reveals distinct inductive abilities of stromal cells from benign prostatic hyperplasia and prostate cancer. Endocrinology 146 13–18

    Article  CAS  PubMed  Google Scholar 

  • Barzgar Barough N, Sajjadian F, Jalilzadeh N, Shafaei H and Velaei K 2021 Understanding breast cancer heterogeneity through non-genetic heterogeneity. Breast Cancer 28 777–791

    Article  PubMed  Google Scholar 

  • Baudrimont A, Jaquet V, Wallerich S, Voegeli S and Becksei A 2019 Contribution of RNA degradation to intrinsic and extrinsic noise in gene expression. Cell Rep. 26 3752–3761

    Article  CAS  PubMed  Google Scholar 

  • Beadle GW and Tatum EL 1941 Genetic control of biochemical reactions in neurospora. Proc. Natl. Acad. Sci. USA 27 499–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bell CC, Fennell KA, Chan Y-C, et al. 2019 Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nat. Commun. 10 2723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bell CC and Gilan O 2020 Principles and mechanisms of non-genetic resistance in cancer. Br. J. Cancer 122 465–472

    Article  PubMed  Google Scholar 

  • Berking C, Takemoto R, Satyamoorthy K, et al. 2004 Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B. Cancer Res. 64 807–811

    Article  CAS  PubMed  Google Scholar 

  • Bhatia S, Wang P, Toh A and Thompson EW 2020 New insights into the role of phenotypic plasticity and EMT in driving cancer progression. Front. Mol. Biosci. 7 1–18

    Article  CAS  Google Scholar 

  • Biddle A, Gammon L, Liang X, Costea DE and Mackenzie IC 2016 Phenotypic plasticity determines cancer stem cell therapeutic resistance in oral squamous cell carcinoma. EBioMedicine 4 138–145

    Article  PubMed  PubMed Central  Google Scholar 

  • Biddle A, Liang X, Gammon L, et al. 2011 Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 71 5317–5326

    Article  CAS  PubMed  Google Scholar 

  • Bierie B, Pierce SE, Kroeger C, et al. 2017 Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc. Natl. Acad. Sci. USA 114 E2337–2346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biswas A and De S 2021 Drivers of dynamic intratumour heterogeneity and phenotypic plasticity. Am. J. Physiol. Cell Physiol. 320 C750–C760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biswas K, Jolly MK and Ghosh A 2019 Stability and mean residence times for hybrid epithelial/mesenchymal phenotype. Phys. Biol. 16 025003

    Article  CAS  PubMed  Google Scholar 

  • Blake W, Balázsi G, Kohanski M, et al. 2006 Phenotypic consequences of promoter-mediated transcriptional noise. Mol. Cell 24 853–865

    Article  CAS  PubMed  Google Scholar 

  • Bocci F, Gearhart-Serna L, Boareto M, et al. 2019 Toward understanding cancer stem cell heterogeneity in the tumour microenvironment. Proc. Natl. Acad. Sci. USA 116 148–157

    Article  CAS  PubMed  Google Scholar 

  • Bocci F, Jolly MK, Tripathi SC, et al. 2017 Numb prevents a complete epithelial-mesenchymal transition by modulating Notch signalling. J. R. Soc. Interface 14 20170512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bocci F, Mandal S, Tejaswi T and Jolly MK 2021 Investigating epithelial‐mesenchymal heterogeneity of tumours and circulating tumour cells with transcriptomic analysis and biophysical modeling. Comput. Syst. Oncol. 1 e1015

    Google Scholar 

  • Bocci F, Tripathi SC, Vilchez MSA, et al. 2019b NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype. Integr. Biol. 11 251–263

    Article  Google Scholar 

  • Boumahdi S and de Sauvage FJ 2020 The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19 39–56

    Article  CAS  PubMed  Google Scholar 

  • Brabletz S and Brabletz T 2010 The ZEB/miR-200 feedback loop—a motor of cellular plasticity in development and cancer? EMBO Rep. 11 670–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brandman O and Meyer T 2008 Feedback loops shape cellular signals in space and time. Science 322 390–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brauner A, Fridman O, Gefen O and Balaban NQ 2016 Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nat. Rev. Microbiol. 14 320–330

    Article  CAS  PubMed  Google Scholar 

  • Brock A, Chang H and Huang S 2009 Non-genetic heterogeneity—a mutation-independent driving force for the somatic evolution of tumours. Nat. Rev. Genet. 10 336–342

    Article  CAS  PubMed  Google Scholar 

  • Brown MS, Abdollahi B, Wilkins OM, et al. 2021 Dynamic plasticity within the EMT spectrum, rather than static mesenchymal traits, drives tumour heterogeneity and metastatic progression of breast cancers. bioRxiv. https://doi.org/10.1101/2021.03.17.434993

    Article  PubMed  PubMed Central  Google Scholar 

  • Buecker C and Wysocka J 2012 Enhancers as information integration hubs in development: lessons from genomics. Trends Genet .28 276–284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bussard KM, Boulanger CA, Booth BW, Bruno RD and Smith GH 2010 Reprogramming human cancer cells in the mouse mammary gland. Cancer Res. 70 6336–6343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cameron MD, Schmidt EE, Kerkvliet N, et al. 2000 Temporal progression of metastasis in lung: Cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res. 60 2541–2546

    CAS  PubMed  Google Scholar 

  • Cassidy T, Nichol D, Robertson-Tessi M, Craig M and Anderson ARA 2021 The role of memory in non-genetic inheritance and its impact on cancer treatment resistance. PLoS Comput. Biol. 17 e1009348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Celià-Terrassa T, Bastian C, Liu DD, et al. 2018 Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat. Commun. 9 5005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Celià-Terrassa T and Jolly MK 2020 Cancer stem cells and epithelial-to-mesenchymal transition in cancer metastasis. Cold Spring Harb. Perspect. Med. 10 a036905

    Article  CAS  Google Scholar 

  • Celià-Terrassa T and Kang Y 2016 Distinctive properties of metastasis-initiating cells. Genes Dev. 30 892–908

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Celià-Terrassa T, Meca-Cortés Ó, Mateo F, et al. 2012 Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumour-initiating cells. J. Clin. Investig. 122 1849–1868

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chakrabortee S, Meersman F, Kaminski Schierle GS, et al. 2010 Catalytic and chaperone-like functions in an intrinsically disordered protein associated with desiccation tolerance. Proc. Natl. Acad. Sci. USA 107 16084–16089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang HH, Hemberg M, Barahona M, Ingber DE and Huang S 2008 Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453 544–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen L, Gibbons DL, Goswami S, et al. 2014 Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoural immunosuppression. Nat. Commun. 5 5241

    Article  CAS  PubMed  Google Scholar 

  • Chen WL, Wang CC, Lin YJ, Wu CP and Hsieh CH 2015 Cycling hypoxia induces chemoresistance through the activation of reactive oxygen species-mediated B-cell lymphoma extra-long pathway in glioblastoma multiforme. J. Transl. Med. 13 389

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chouaib S, Janji B, Tittarelli A, Eggermont A and Thiery JP 2014 Tumour plasticity interferes with anti-tumour immunity. Crit. Rev. Immunol. 34 91–102

    Article  CAS  PubMed  Google Scholar 

  • Cieply B, Riley P IV, Pifer PM, et al. 2012 Suppression of the epithelial-mesenchymal transition by grainyhead-like-2. Cancer Res. 72 2440–2453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colacino JA, Azizi E, Brooks MD, et al. 2018 Heterogeneity of human breast stem and progenitor cells as revelaed by transcriptional profiling. Stem Cell Rep. 10 1596–1609

    Article  CAS  Google Scholar 

  • Cook DP and Vanderhyden BC 2020 Context specificity of the EMT transcriptional response. Nat. Commun. 11 2142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalerba P, Kalisky T, Sahoo D, et al. 2011 Single-cell dissection of transcriptional heterogeneity in human colon tumours. Nat. Biotechnol. 29 1120–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davidson CJ and Surette MG 2008 Individuality in Bacteria. Annu. Rev. Genet. 42 253–268

    Article  CAS  PubMed  Google Scholar 

  • Deshmukh AP, Vasaikar SV, Tomczak K, et al. 2021 Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing. Proc. Natl. Acad. Sci. USA 118 e2102050118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devaraj V and Bose B 2019 Morphological state transition dynamics in EGF-induced epithelial to mesenchymal transition. J. Clin. Med. 8 911

    Article  CAS  PubMed Central  Google Scholar 

  • Dhar R, Missarova AM, Lehner B and Carey LB 2019 Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation. eLife 8 e38904

    Article  PubMed  PubMed Central  Google Scholar 

  • Dirkse A, Golebiewska A, Buder T, et al. 2019 Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumour plasticity shaped by the microenvironment. Nat. Commun. 10 1787

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Domingues AF, Kulkarni R, Giotopoulos G, et al. 2020 Loss of KAT2A enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells. eLife 9 e51754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dongre A, Rashidian M, Reinhardt F, et al. 2017 Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77 3982–3989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duda DG, Duyverman AMMJ, Kohno M, et al. 2010 Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl. Acad. Sci. USA 107 21677–21682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Echeverria GV, Ge Z, Seth S, et al. 2019 Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci. Transl. Med. 11 eaav0936 

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elowitz MB, Levine AJ, Siggia ED and Swain PS 2002 Stochastic gene expression in a single cell. Science 297 1183–1186

    Article  CAS  PubMed  Google Scholar 

  • Evans TD and Zhang F 2020 Bacterial metabolic heterogeneity: origins and applications in engineering and infectious disease. Curr. Opin. Biotechnol. 64 183–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farquhar KS, Charlebois DA, Szenk M, et al. 2019 Role of network-mediated stochasticity in mammalian drug resistance. Nat. Commun. 10 2766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feinberg AP, Koldobskiy MA and Gondor A 2016 Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17 284–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng J, Kessler DA, Ben-Jacob E and Levine H 2014 Growth feedback as a basis for persister bistability. Proc. Natl. Acad. Sci. USA 111 544–549

    Article  CAS  PubMed  Google Scholar 

  • Ferguson B, Handoko HY, Mukhopadhyay P, et al. 2019 Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma. eLife 8 e42424 

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferrell JE 2012 Bistability, bifurcations, and waddington’s epigenetic landscape. Curr. Biol. 22 R458–R466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fierst JL 2011 A history of phenotypic plasticity accelerates adaptation to a new environment. J. Evolut. Biol. 24 1992–2011

    Article  CAS  Google Scholar 

  • Font-Clos F, Zapperi S and La Porta CAM 2018 Topography of epithelial–mesenchymal plasticity. Proc. Natl. Acad. Sci. USA 115 5902–5907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedrich D, Friedel L, Finzel A, et al. 2019 Stochastic transcription in the p53-mediated response to DNA damage is modulated by burst frequency. Mol. Syst. Biol. 15 e9068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukaya T, Lim B and Levine M 2016 Enhancer control of transcriptional bursting. Cell 166 358–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furumaya C, Martinez-Sanz P, Bouti P, Kuijpers TW and Matlung HL 2020 Plasticity in pro- and anti-tumour activity of neutrophils: shifting the balance. Front. Immunol. 11 2100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Genovese G, Kähler AK, Handsaker RE, et al. 2014 Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371 2477–2487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • George JT, Jolly MK, Xu S, Somarelli JA and Levine H 2017 Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric. Cancer Res. 77 6415–6428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, et al. 2012 Intratumour heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366 883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerosa L, Chidley C, Froehlich F, et al. 2020 Receptor-driven ERK pulses reconfigure MAPK signaling and enable persistence of drug-adapted BRAF-Mutant melanoma cells. Cell Syst. 11 478–494.e9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillespie DT 2007 Stochastic simulation of chemical kinetics. Annu. Rev. Phys. Chem. 58 35–55

  • Goetz H, Melendez-Alvarez JR, Chen L and Tian X-J 2020 A plausible accelerating function of intermediate states in cancer metastasis. PLOS Comput. Biol. 16 e1007682

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gopalan V, Singh A, Mehrabadi FR, et al. 2021 A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and PDAC. Cancer Res. 81 3958–3970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goury-Sistla P, Nanjundiah V and Pande G 2012 Bimodal distribution of motility and cell fate in Dictyostelium discoideum. Int. J. Dev. Biol. 56 263–272

    Article  CAS  PubMed  Google Scholar 

  • Greaves M and Maley CC 2012 Clonal evolution in cancer. Nature 481 306–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grosse-Wilde A, Fouquier d’ Herouei A, McIntosh E, et al. 2015 Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLoS One 10 e0126522

  • Guinn MT, Wan Y, Levovitz S, et al. 2020 Observation and control of gene expression noise: barrier crossing analogies between drug resistance and metastasis. Front. Genet. 11 586726

    Article  PubMed  PubMed Central  Google Scholar 

  • Gunnarssson EB, De S, Leder K and Foo J 2020 Understanding the role of phenotypic switching in cancer drug resistance. J. Theor. Biol. 490 110162

    Article  CAS  Google Scholar 

  • Gupta PB, Fillmore CM, Jiang G, et al. 2011 Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146 633–644

    Article  CAS  PubMed  Google Scholar 

  • Gupta PB, Pastushenko I, Skibinski A, Blanpain C and Kuperwasser C 2019 Phenotypic plasticity: driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell 24 65–78

    Article  CAS  PubMed  Google Scholar 

  • Haas D, Ablin AR, Miller C, Zoger S and Matthay KK 1988 Complete pathologic maturation and regression of stage IVS neuroblastoma without treatment. Cancer 62 818–825

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D and Weinberg RA 2011 Hallmarks of cancer: The next generation. Cell 144 646–674

    Article  CAS  PubMed  Google Scholar 

  • Hangauer MJ, Viswanathan VS, Ryan MJ, et al. 2017 Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551 247–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hari K, Sabuwala B, Subramani BV, et al. 2020 Identifying inhibitors of epithelial–mesenchymal plasticity using a network topology-based approach. NPJ Syst. Biol. Appl. 6 15

    Article  PubMed  PubMed Central  Google Scholar 

  • Harms A, Maisonneuve E and Gerdes K 2016 Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 354 aaf4268

    Article  PubMed  CAS  Google Scholar 

  • Hayford CE, Tyson DR, Robbins CJ, et al. 2021 An in vitro model of tumour heterogeneity resolves genetic, epigenetic, and stochastic sources of cell state variability. PLoS Biol. 19 e3000797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haynes C, Oldfield CJ, Ji F, et al. 2006 Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput. Biol. 2 e100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hendy O, Campbell J, Weissman JD, Larson DR and Singer DS 2017 Differential context-specific impact of individual core promoter elements on transcriptional dynamics. Mol. Biol. Cell 28 3360–3370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirata A, Hatano Y, Niwa M, Hara A and Tomita H 2019 Heterogeneity in colorectal cancer stem cells. Cancer Prev. Res. 12 413–420

    Article  CAS  Google Scholar 

  • Hong SP, Chan TE, Lombardo Y, et al. 2019 Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy. Nat. Commun. 10 3840

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hong T, Watanabe K, Ta CH, et al. 2015 An Ovol2-Zeb1 mutual inhibitory circuit governs bidirectional and multi-step transition between epithelial and mesenchymal states. PLoS Comput. Biol. 11 e1004569

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hornung G, Bar-Ziv R, Rosin D, et al. 2012 Noise-mean relationship in mutated promoters. Genome Res. 22 2409–2417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Z, Artibani M, Alsaadi A, et al. 2020 The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells. Cancer Cell 37 226–242.e7

    Article  CAS  PubMed  Google Scholar 

  • Huang RY-J, Wong MK, Tan TZ, et al. 2013 An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis. 4 e915

  • Huang S, Enrberg I and Kauffman SA 2009 Cancer attractors: a systems view of tumours from a gene network dynamics and developmental perspective. Semin. Cell Dev. Biol. 20 869–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huh D and Paulsson J 2011 Non-genetic heterogeneity from stochastic partitioning at cell division. Nat. Genet. 43 95–100

    Article  CAS  PubMed  Google Scholar 

  • Hutton C, Heider F, Blanco-Gomez A, et al. 2021 Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumour immunity. Cancer Cell 39 1227–1244.e20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia D, Jolly MK, Kulkarni P and Levine H 2017 Phenotypic plasticity and cell fate decisions in cancer: Insights from dynamical systems theory. Cancers 9 E70

    Article  PubMed  CAS  Google Scholar 

  • Jia D, Park JH, Kaur H, et al. 2021 Towards decoding the coupled decision-making of metabolism and epithelial-to-mesenchymal transition in cancer. Br. J. Cancer 124 1902–1911

    Article  PubMed  PubMed Central  Google Scholar 

  • Jia W, Deshmukh A, Mani SA, Jolly MK and Levine H 2019 A possible role for epigenetic feedback regulation in the dynamics of the Epithelial-Mesenchymal Transition (EMT). Phys. Biol. 16 066004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jolly MK, Huang B, Lu M, et al. 2014 Towards elucidating the connection between epithelial-mesenchymal transitions and stemness. J. R. Soc. Interface 11 20140962

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jolly MK, Jia D, Boareto M, et al. 2015 Coupling the modules of EMT and stemness: A tunable stemness window model. Oncotarget 6 25161–25174

    Article  PubMed  PubMed Central  Google Scholar 

  • Jolly MK, Kulkarni P, Weninger K, Orban J and Levine H 2018a Phenotypic plasticity, bet-hedging, and androgen independence in prostate cancer: role of non-genetic heterogeneity. Front. Oncol. 8 50

    Article  PubMed  PubMed Central  Google Scholar 

  • Jolly MK, Mani SA and Levine H 2018b Hybrid epithelial/mesenchymal phenotype(s): The ‘fittest’ for metastasis? Biochim. Biophys. Acta Rev. Cancer 1870 151–157

  • Kang X, Wang J and Li C 2019 Exposing the underlying relationship of cancer metastasis to metabolism and epithelial-mesenchymal transitions. iScience 21 754–772

  • Karacosta LG, Anchang B, Ignatiadis N, et al. 2019 Mapping lung cancer epithelial-mesenchymal transition states and trajectories with single-cell resolution. Nat. Commun. 10 5587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karki P, Angardi V, Mier JC and Orman MA 2021 A transient metabolic state in melanoma persister cells mediated by chemotherapeutic treatments. bioRxiv 432154

  • Kasemeier-Kulesa JC, Teddy JM, Postovit LM, et al. 2008 Reprogramming multipotent tumour cells with the embryonic neural crest microenvironment. Dev. Dyn. 237 2657–2666

    Article  PubMed  PubMed Central  Google Scholar 

  • Kazanets A, Shorstova T, Hilmi K, Marques M and Witcher M 2016 Epigenetic silencing of tumour suppressor genes: Paradigms, puzzles, and potential. Biochim. Biophysi. Acta Rev. Cancer 1865 275–288

  • Kennedy SR, Zhang Y and Risques RA 2019 Cancer-associated mutations but no cancer: insights into the early steps of carcinogenesis and implications for early cancer detection. Trends Cancer 5 531–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krebs AM, Mitschke J, Losada ML, et al. 2017 The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19 518–529

    Article  CAS  PubMed  Google Scholar 

  • Krimmel JD, Schmitt MW, Harrell MI, et al. 2016 Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues. Proc. Natl. Acad. Sci. USA 113 6005–6010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kröger C, Afeyan A, Mraz J, et al. 2019 Acquisition of a hybrid E/M state is essential for tumourigenicity of basal breast cancer cells. Proc. Natl. Acad. Sci. USA 116 7353–7362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kulkarni P, Jolly MK, Jia D, et al. 2017 Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity. Proc. Natl. Acad. Sci. USA 114 E2644–E2653

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar N, Singh A and Kulkarni RV 2015 Transcriptional bursting in gene expression: analytical results for general stochastic models. PLoS Comput. Biol. 11 e1004292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kvokackova B, Remsik J, Jolly MK and Soucek K 2021 Phenotypic heterogeneity of triple-negative breast cancer mediated by epithelial-mesenchymal plasticity. Cancers 13 2188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lang J, Nie Q and Li C 2021 Landscape and kinetic path quantify critical transitions in epithelial-mesenchymal transition. Biophys. J. 120 4484–4500

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Lee J, Farquhar KS, et al. 2014 Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions. Proc. Natl. Acad. Sci. USA  111  E364–E373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis AC and Kats LM 2021 Non-genetic heterogeneity, altered cell fate and differentiation therapy. EMBO Mol. Med. 13 e12670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C and Balazsi G 2018 A landscape view on the interplay between EMT and cancer metastasis. NPJ Syst. Biol. Appl. 4 34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li S, Giardina DM and Siegal ML 2018 Control of nongenetic heterogeneity in growth rate and stress tolerance of Saccharomyces cerevisiae by cyclic AMP-regulated transcription factors. PLoS Genet. 14 e1007744

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li X, Jolly MK, George JT, Pienta KJ and Levine H 2019 Computational modeling of the crosstalk between macrophage polarization and tumour cell plasticity in the tumour microenvironment. Front. Oncol. 9 10

    Article  PubMed  PubMed Central  Google Scholar 

  • Lichtenstein AV 2018 Genetic mosaicism and cancer: cause and effect. Cancer Res. 78 1375–1378

    Article  CAS  PubMed  Google Scholar 

  • Lin X, Kulkarni P, Bocci F, et al. 2019 Structural and dynamical order of a disordered protein: Molecular insights into conformational switching of PAGE4 at the systems level. Biomolecules 9 77

    Article  CAS  PubMed Central  Google Scholar 

  • Lin X, Roy S, Jolly MK, et al. 2018 PAGE4 and conformational switching: insights from molecular dynamics simulations and implications for prostate cancer. J. Mol. Biol.  430 2422–2438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, Liu W, Wang L, et al. 2017 Hypoxia-inducible factor 1 mediates intermittent hypoxia-induced migration of human breast cancer MDA-MB-231 cells. Oncol. Lett. 14 7715–7722

    PubMed  PubMed Central  Google Scholar 

  • Liu S, Cong Y, Wang D, et al. 2014 Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2 78–91

    Article  CAS  Google Scholar 

  • Liu Z, Chen M, Zhao R, et al. 2019 CAF-induced placental growth factor facilitates neoangiogenesis in hepatocellular carcinoma. Acta Biochim. Biophys. Sin. 52 18–25

    Article  CAS  Google Scholar 

  • Louie E, Nik S, Chen J, et al. 2010 Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res. 12 R94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu M, Jolly MK, Levine H, Onuchic JN and Ben-Jacob E 2013 MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination. Proc. Natl. Acad. Sci. USA 110 18144–18149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luzzi KJ, MacDonald IC, Schmidt EE, et al. 1998 Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 153 865–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyberopoulou A, Aravantinos G, Efstathopoulos EP, et al 2015 Mutational analysis of circulating tumour cells from colorectal cancer patients and correlation with primary tumour tissue. PLoS One 10 e0123902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mack SC, Witt H, Piro RM, et al. 2014 Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506 445–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maffini MV, Calabro JM, Soto AM and Sonnenschein C 2005 Stromal regulation of neoplastic development: Age-dependent normalization of neoplastic mammary cells by mammary stroma. Am. J. Pathol. 167 1405–1410

    Article  PubMed  PubMed Central  Google Scholar 

  • Maffini MV, Soto AM, Calabro JM, Ucci AA and Sonnenschein C 2004 The stroma as a crucial target in rat mammary gland carcinogenesis. J. Cell Sci. 117 1495–1502

    Article  CAS  PubMed  Google Scholar 

  • Mahmoudabadi G, Rajagopalan K, Getzenberg RH, et al 2013 Intrinsically disordered proteins and conformational noise Implications in cancer. Cell Cycle 12 26–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mani SA, Guo W, Liao M-J, et al. 2008 The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133 704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantovani F, Collavin L and Del Sal G 2019 Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 26 199–212

    Article  PubMed  Google Scholar 

  • Marine J-C, Dawson S-J and Dawson MA 2020 Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20 743–756

    Article  CAS  PubMed  Google Scholar 

  • Mcadams HH and Arkin A 1997 Stochastic mechanisms in gene expression. Proc. Natl. Acad. Sci. USA 94 814–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCullough KD, Coleman WB, Smith GJ and Grisham JW 1997 Age-dependent induction of hepatic tumour regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Res. 57 1807–1813

    CAS  PubMed  Google Scholar 

  • McGranahan N and Swanton C 2017 Clonal heterogeneity and tumour evolution: past, present, and the future. Cell 168 613–628

    Article  CAS  PubMed  Google Scholar 

  • Mikubo M, Inoue Y, Liu G and Tsao M-S 2021 Mechanism of drug tolerant persister cancer cells: the landscape and clinical implication for therapy. J. Thorac. Oncol. 16 1798–1809

    Article  CAS  PubMed  Google Scholar 

  • Mintz B and Illmensee K 1975 Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl. Acad. Sci. USA 72 3585–3589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miura H, Kondo Y, Matsuda M and Aoki K 2018 Cell-to-cell heterogeneity in p38-mediated cross-inhibition of JNK causes stochastic cell death. Cell Rep. 24 2658–2668

    Article  CAS  PubMed  Google Scholar 

  • Mooney SM, Jolly MK, Levine H and Kulkarni P 2016 Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins. Asian J. Androl. 18 704–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moris N, Pina C and Arias AM 2016 Transition states and cell fate decisions in epigenetic landscapes. Nat. Rev. Genet. 17 693–703

    Article  CAS  PubMed  Google Scholar 

  • Moyed HS and Bertrand KP 1983 hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155 768–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nieto MA, Huang RY, Jackson RA and Thiery JP 2016 EMT: 2016. Cell 166 21–45

    Article  CAS  PubMed  Google Scholar 

  • Nihan AK, Sugiyama N, Reddy Kalathur RK, et al. 2019 Histone deacetylases, Mbd3/NuRD, and Tet2 hydroxylase are crucial regulators of epithelial–mesenchymal plasticity and tumour metastasis. Oncogene 39 1498–1513

    Article  CAS  Google Scholar 

  • Niklas KJ, Dunker AK and Yruela I 2018 The evolutionary origins of cell type diversification and the role of intrinsically disordered proteins. J. Exp. Bot. 69 1437–1446

    Article  CAS  PubMed  Google Scholar 

  • Nowell P 1976 The clonal evolution of tumour cell populations. Science 194 23–28

    Article  CAS  PubMed  Google Scholar 

  • Ocaña OH, Córcoles R, Fabra A, et al. 2012 Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22 709–724

    Article  PubMed  CAS  Google Scholar 

  • Oren Y, Tsabar M, Cuoco MS, et al. 2021 Cycling cancer persister cells arise from lineages with distinct programs. Nature 596 576–582

    Article  PubMed  CAS  Google Scholar 

  • Osorio D, Yu X, Zhong Y, et al. 2020 Single-cell expression varibility implies cell function. Cells 9 14

    Article  CAS  Google Scholar 

  • Paek AL, Liu JC, Loewer A, Forrester WC and Lahav G 2016 Cell-to-cell variation in p53 dynamics leads to fractional killing. Cell 165 631–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paget S 1889 The distribution of secondary growths in cancer of the breast. Lancet 133 571–573

    Article  Google Scholar 

  • Pasani S, Sahoo S and Jolly MK 2021 Hybrid E/M phenotype(s) and stemness: a mechanistic connection embedded in network topology. J. Clin. Med. 10 60

    Article  CAS  Google Scholar 

  • Pastushenko I and Blanpain C 2019 EMT transition states during tumour progression and metastasis. Trends Cell Biol. 29 212–226

    Article  CAS  PubMed  Google Scholar 

  • Pastushenko I, Brisebarre A, Sifrim A, et al. 2018 Identification of the tumour transition states occurring during EMT. Nature 556 463–468

    Article  CAS  PubMed  Google Scholar 

  • Patil A, Kinoshita K and Nakamura H 2010 Hub Promiscuity in protein-protein interaction networks. Int. J. Mol. Sci. 11 1930–1943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pearson GW 2019 Control of invasion by epithelial-to-mesenchymal transition programs during metastasis. J. Clin. Med. 8 646

    Article  CAS  PubMed Central  Google Scholar 

  • Pillai M and Jolly MK 2021 Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma. iScience 24 103111

    Article  PubMed  PubMed Central  Google Scholar 

  • Pisco AO and Huang S 2015 Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me.’ Br. J. Cancer 112 1725–1732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prieto-Vila M, Usuba W, Takahashi R, et al. 2019 Single-cell analysis reveals a preexisting drug-resistant subpopulation in the luminal breast cancer subtype. Cancer Res. 79 4412–4425

    Article  CAS  PubMed  Google Scholar 

  • Qin S, Jiang J, Lu Y, et al. 2020 Emerging role of tumour cell plasticity in modifying therapeutic response. Signal Transduct. Target. Ther. 5 228

    Article  CAS  Google Scholar 

  • Quail DF and Joyce JA 2013 Microenvironmental regulation of tumour progression and metastasis. Nat. Med. 19 1423–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raj A, Peskin CS, Tranchina D, Vargas DY and Tyagi S 2006 Stochastic mRNA synthesis in mammalian cells. PLoS Biol. 4 e309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rambow F, Rogiers A, Marin-Bejar O, et al. 2018 Toward minimal residual disease-directed therapy in melanoma. Cell 174 843–855.e59

    Article  CAS  PubMed  Google Scholar 

  • Ramirez M, Rajaram S, Steininger RJ, et al. 2016 Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 7 10690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raser JM and O’Shea EK 2004 Control of stochasticity in eukaryotic gene expression. Science 304 1811–1814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ravasio A, Myaing MZ, Chia S, et al. 2020 Single-cell analysis of EphA clustering phenotypes to probe cancer cell heterogeneity. Commun. Biol. 3 429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebecca VW and Herlyn M 2020 Nongenetic mechanisms of drug resistance in melanoma. Annu. Rev. Cancer Biol. 4 315–330

    Article  Google Scholar 

  • Rehman SK, Haynes J, Collignon E, et al. 2021 Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184 226–242.e21

    Article  CAS  PubMed  Google Scholar 

  • Roca H, Hernandez J, Weidner S, et al. 2013 Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One 8 e76773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossi NA, El Meouche I and Dunlop MJ 2019 Forecasting cell fate during antibiotic exposure using stochastic gene expression. Commun. Biol. 2 259

    Article  PubMed  PubMed Central  Google Scholar 

  • Rudnick JA, Arendt LM, Klebba I, et al. 2011 Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells. PLoS One 6 e24605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruscetti M, Dadashian EL, Guo W, et al. 2016 HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35 3781–3795

    Article  CAS  PubMed  Google Scholar 

  • Sacchetti A, Teeuwssen M, Verhagen M, et al. 2021 Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer. eLife 10 e61461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sahoo S, Mishra A, Kaur H, et al. 2021a A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells. NAR Cancer 3 zcab027

  • Sahoo S, Nayak SP, Hari K, et al. 2021b Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype. Front. Immunol. 12 1664–3224

    Article  Google Scholar 

  • Sahoo S, Singh D, Chakraborty P and Jolly MK 2020 Emergent properties of the HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD. J. Clin. Med. 9 870

    Article  CAS  PubMed Central  Google Scholar 

  • Salgia R and Kulkarni P 2018 The genetic/non-genetic duality of drug “resistance”  in cancer. Trends Cancer 4 110–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarkar S, Sinha SK, Levine H, Jolly MK and Dutta PS 2019 Anticipating critical transitions in epithelial-hybrid-mesenchymal cell-fate determination. Proc. Natl. Acad. Sci. USA 116 26343–26352

    Article  CAS  PubMed Central  Google Scholar 

  • Sasagawa Y, Nikaido I, Hayashi T, et al. 2013 Quartz-Seq: A highly reproducible and sensitive single-cell RNA sequencing method, reveals nongenetic gene-expression heterogeneity. Genome Biol. 14 3097

    Article  CAS  Google Scholar 

  • Saxena K and Jolly MK 2019 Acute vs. Chronic vs. cyclic hypoxia: Their differential dynamics, molecular mechanisms, and effects on tumour progression. Biomolecules 9 339

    Article  CAS  PubMed Central  Google Scholar 

  • Saxena K, Srikrishnan S, Celia-Terrassa T and Jolly MK 2020 OVOL1/2: Drivers of epithelial differentiation in development, disease, and reprogramming. Cells Tissues Organs 211 183–192

    CAS  Google Scholar 

  • Schliekelman MJ, Taguchi A, Zhu J, et al. 2015 Molecular portraits of epithelial, mesenchymal, and hybrid states in lung adenocarcinoma and their relevance to survival. Cancer Res. 75 1789–1800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serresi M, Kertalli S, Li L, Schmitt MJ, Dramaretska Y, Wierikx J, Hulsman D and Gargiulo G 2021 Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition. Sci. Adv. 7 eabd7974

  • Sha Y, Wang S, Zhou P and Nie Q 2020 Inference and multiscale model of epithelial-to-mesenchymal transition via single-cell transcriptomic data. Nucleic Acids Res. 48 9505–9520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shachaf CM and Felsher DW 2005 Rehabilitation of cancer through oncogene inactivation. Trends Mol. Med. 11 316–321

    Article  CAS  PubMed  Google Scholar 

  • Shachaf CM, Kopelman AM, Arvanitis C, et al. 2004 MYC Inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431 1112–1117

    Article  CAS  PubMed  Google Scholar 

  • Shaffer SM, Dunagin MC, Torborg SR, et al. 2017 Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546 431–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shafran JS, Jafari N, Casey AN, Győrffy B and Denis GV 2021 BRD4 regulates key transcription factors that drive epithelial–mesenchymal transition in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 24 268–277

    Article  CAS  PubMed  Google Scholar 

  • Sharma A, Merritt E, Hu X, et al. 2019 Non-genetic intra-tumour heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumours. Cell Rep. 29 2164–2174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma SV, Lee DY, Li B, et al. 2010 A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141 69–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen S, Faouzi S, Souquere S, et al. 2020a Melanoma persister cells are tolerant to BRAF/MEK inhibitors via ACOX1-mediated fatty acid oxidation. Cell Rep. 33 108421

    Article  CAS  PubMed  Google Scholar 

  • Shen S, Vagner S and Robert C 2020b Persistent cancer cells: the deadly survivors. Cell 183 860–874

    Article  CAS  PubMed  Google Scholar 

  • Shibue T and Weinberg RA 2017 EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 14 611–629

    Article  PubMed  PubMed Central  Google Scholar 

  • Shlyakhtina Y, Moran KL and Portal MM 2021 Genetic and non-genetic mechanisms underlying cancer evolution. Cancers 13 1380

    Article  PubMed  PubMed Central  Google Scholar 

  • Sigal A, Milo R, Cohen A, et al. 2006 Variability and memory of protein levels in human cells. Nature 444 643–646

    Article  CAS  PubMed  Google Scholar 

  • Simeonov KP, Byrns CN, Clark ML, et al. 2021 Single-cell lineage and transcriptome reconstruction of metastatic cancer reveals selection of aggressive hybrid EMT states. Cancer Cell 39 1150–1162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh A, Razooky BS, Dar RD and Weinberger LS 2012 Dynamics of protein noise can distinguish between alternate sources of gene-expression variability. Mol. Syst. Biol. 8 607

    Article  PubMed  PubMed Central  Google Scholar 

  • Singh D, Bocci F, Kulkarni P and Jolly MK 2021 Coupled feedback loops involving PAGE4, EMT and Notch signaling can give rise to non-genetic heterogeneity in prostate cancer cells. Entropy 26 288

    Article  CAS  Google Scholar 

  • Sonnenschein C and Soto AM 2015 Cancer metastases: So close and so far. J. Natl. Cancer Inst. 107 17–20

    Article  Google Scholar 

  • Sonnenschein C, Soto AM, Rangarajan A and Kulkarni P 2014 Competing views on cancer. J. Biosci. 39 281–302

    Article  PubMed  PubMed Central  Google Scholar 

  • Soto AM and Sonnenschein C 2011 The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. BioEssays 33 332–340

    Article  PubMed  PubMed Central  Google Scholar 

  • Specht H, Emmott E, Koller T and Slavov N 2019 High-throughput single-cell proteomics quantifies the emergence of macrophage heterogeneity. bioRxiv 665307

  • Spencer SL, Gaudet S, Albeck JG, Burke JM and Sorger PK 2009 Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459 428–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Staby L, O’Shea C, Willemoës M, Theisen F, Kragelund BB and Skriver K 2017 Eukaryotic transcription factors: Paradigms of protein intrinsic disorder. Biochem. J. 474 2509–2532

    Article  CAS  PubMed  Google Scholar 

  • Steinway SN, Zañudo JGT, Michel PJ, et al. 2015 Combinatorial interventions inhibit TGFβ-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes. NPJ Syst. Biol. Appl. 1 15014

  • Stylianou N, Lehman ML, Wang C, et al. 2019 A molecular portrait of epithelial–mesenchymal plasticity in prostate cancer associated with clinical outcome. Oncogene 38 913–934

    Article  CAS  PubMed  Google Scholar 

  • Su Y, Bintz M, Yang Y, et al. 2019 Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance. PLoS Comput. Biol. 15 e1007034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su Y, Wei W, Robert L, et al. 2017 Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc. Natl. Acad. Sci. USA 114 13679–13684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subbalakshmi AR, Kundnani D, Biswas K, et al. 2020 NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype. Front. Oncol. 10 1794

    Article  Google Scholar 

  • Süel GM, Garcia-Ojalvo J, Liberman L and Elowitz MB 2006 An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440 545–550

    Article  PubMed  CAS  Google Scholar 

  • Tan TZ, Miow QH, Miki Y, et al. 2014 Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol. Med. 6 1279–1293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang DG 2012 Understanding cancer stem cell heterogeneity and plasticity. Cell Res. 22 457–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tantale K, Mueller F, Kozulic-Pirher A, et al. 2016 A single-molecule view of transcription reveals convoys of RNA polymerases and multi-scale bursting. Nat. Commun. 7 12248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarin D 2011 Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance. Semin. Cancer Biol. 21 72–82

    Article  CAS  PubMed  Google Scholar 

  • Thankamony AP, Saxena K, Murali R, Jolly MK and Nair R 2020 Cancer stem cell plasticity—a deadly deal. Front. Mol. Biosci. 7 79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian X-J, Zhang H and Xing J 2013 Coupled reversible and irreversible bistable switches underlying TGFβ-induced epithelial to mesenchymal transition. Biophys. J. 105 1079–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tièche CC, Gao Y, Bührer ED, et al. 2018 Tumour initiation capacity and therapy resistance are differential features of emt-related subpopulations in the NSCLC cell line A549. Neoplasia 21 185–196

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tirosh I, Izar B, Prakadan SM, et al. 2016 Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352 189–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toneff MJ, Sreekumar A, Tinnirello A, et al. 2016 The Z-cad dual fluorescent sensor detects dynamic changes between the epithelial and mesenchymal cellular states. BMC Biol. 14 47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tripathi S, Levine H and Jolly MK 2020 The physics of cellular decision-making during epithelial-mesenchymal transition. Annu. Rev. Biophys. 49 1–18

    Article  CAS  PubMed  Google Scholar 

  • Tripathi SC, Peters HL, Taguchi A, et al. 2016 Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc. Natl. Acad. Sci. USA 113 E1555–E1564

    Google Scholar 

  • Tsafou K, Tiwari PB, Forman-Kay JD, Metallo SJ and Toretsky JA 2018 Targeting intrinsically disordered transcription factors: Changing the paradigm. J. Mol. Biol. 430 2321–2341

    Article  CAS  PubMed  Google Scholar 

  • Tyler AL, Asselbergs FW, Williams SM and Moore JH 2009 Shadows of complexity: what biological networks reveal about epistasis and pleiotropy. BioEssays 31 220–227

    Article  PubMed  PubMed Central  Google Scholar 

  • Udyavar AA, Wooten DJ, Hoeksema M, et al. 2017 Novel Hybrid phenotype revealed in small cell lung cancer by a transcription factor network model that can explain tumour heterogeneity. Cancer Res. 77 1063–1074

    Article  CAS  PubMed  Google Scholar 

  • Urban EA and Johnston RJ 2018 Buffering and amplifying transcriptional noise during cell fate specification. Front. Genet. 9 591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Boxtel C, van Heerden JH, Nordholt N, Schmidt P and Bruggeman FJ 2017 Taking chances and making mistakes: non-genetic phenotypic heterogeneity and its consequences for surviving in dynamic environments. J. R. Soc. Interface 14 20170141

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Veening J, Smits WK and Kuipers OP 2008a Bistability, epigenetics, and bet-hedging in bacteria. Annu. Rev. Microbiol. 62 193–212

    Article  CAS  PubMed  Google Scholar 

  • Veening JW, Stewart EJ, Berngruber TW, et al. 2008b Bet-hedging and epigenetic inheritance in bacterial cell development. Proc. Natl. Acad. Sci. USA 105 4393–4398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vega S, Morales AV, Ocaña OH, et al. 2004 Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18 1131–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vander Velde R, Yoon N, Marusyk V, et al. 2020 Resistance to ALK targeting therapies as a gradual Darwinian adaptation to inhibitor specific selective pressures. Nat. Commun. 11 2393

    Article  CAS  Google Scholar 

  • Waddington CH 1957 A discussion of some aspects of theoretical biology; in The strategy of the genes (London: Routledge)

  • Wang J, Zhang K, Xu L and Wang E 2011 Quantifying the Waddington landscape and biological paths for development and differentiation. Proc. Natl. Acad. Sci. USA 108 8257–8262

    Article  CAS  Google Scholar 

  • Wang N, Zheng J, Chen Z, et al. 2019 Single-cell microRNA-mRNA co-sequencing reveals non-genetic heterogeneity and mechanisms of microRNA regulation. Nat. Commun. 10 95

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Watanabe K, Panchy N, Noguchi S, Suzuki H and Hong T 2019 Combinatorial perturbation analysis reveals divergent regulations of mesenchymal genes during epithelial-to-mesenchymal transition. NPJ Syst. Biol. Appl. 5 21

  • Welch DR and Hurst DR 2019 Defining the hallmarks of metastasis. Cancer Res. 79 3011–3027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wooten DJ and Quaranta V 2017 Mathematical models of cell phenotype regulation and reprogramming: Make cancer cells sensitive again! BBA Rev. Cancer 1867 167–175

    CAS  Google Scholar 

  • Xie M, Lu C, Wang J, et al. 2014 Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20 1472–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Mani SA, Donaher JL, et al. 2004 Twist, a master regulator of Morphogenesis, plays an essential role in tumour metastasis. Cell 117 927–939

    Article  CAS  PubMed  Google Scholar 

  • Yeo SK and Guan JL 2017 Breast cancer: multiple subtypes within a tumour? Trends Cancer 3 753–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Youssoufian H and Pyeritz RE 2002 Mechanisms and consequences of somatic mosaicism in humans. Nat. Rev. Genet. 3 748–758

    Article  CAS  PubMed  Google Scholar 

  • Yu M, Bardia A, Wittner BS, et al. 2013 Circulating breast tumour cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339 580–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z and Tjian R 2018 Measuring dynamics of eukaryotic transcription initiation: challenges, insights and opportunities. Transcription 9 159–165

    CAS  PubMed  Google Scholar 

  • Zhang J, Tian X-J, Zhang H, et al. 2014 TGF-β–induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci. Signal. 7 91

    Google Scholar 

  • Zhu Y, Shi C, Zeng L, et al. 2020 High COX-2 expression in cancer-associated fibiroblasts contributes to poor survival and promotes migration and invasiveness in nasopharyngeal carcinoma. Mol. Carcinog. 59 265–280

    Article  CAS  Google Scholar 

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Acknowledgements

MKJ was supported by the Ramanujan Fellowship (SB/S2/RJN-049/2018) awarded by the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), India, and by the Infosys Young Investigator Fellowship awarded by the Infosys Foundation, Bengaluru. Mr. Atchuta Srinivas Duddu (MKJ’s lab) is acknowledged for the artwork for figures 1 and 2.

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  1. Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, 560 012, India

    Kritika Saxena, Ayalur Raghu Subbalakshmi & Mohit Kumar Jolly

  2. Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA

    Prakash Kulkarni

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  1. Kritika Saxena
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Corresponding editor: Susmita Roy

Corresponding editor: Susmita Roy

This article is part of the Topical Collection: Emergent dynamics of biological networks.

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Saxena, K., Subbalakshmi, A.R., Kulkarni, P. et al. Cancer: More than a geneticist’s Pandora’s box. J Biosci 47, 21 (2022). https://doi.org/10.1007/s12038-022-00254-x

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