Abstract
Tumorigenesis is associated with the development of a highly variable pattern of cellular diversity, consequence of genetic and epigenetic diversification, followed by clonal selection and expansion. This process is shaped by the microenvironment and leads to intratumoral heterogeneity, which is characterized by differences between cancer cells in terms of gene expression, phenotypic markers, growth dynamics, and resistance to treatment. Another relevant aspect in intratumor heterogeneity is cell plasticity—the ability of a cell to switch to new identities. In this review, we focus on the mechanisms that regulate cancer cell plasticity within a tumor, and explore the concept of tumor propagating cells, or TPCs, a cancer cell able to propagate/phenocopy the parental tumor and recapitulate tumor heterogeneity. We discuss the influence of the microenvironment and driver mutations on TPCs formation and function, the existence of phenotypically distinct TPC clones within a tumor, the evolution of TPCs with disease progression, and their implications for therapy.
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References
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, et al. The life history of 21 breast cancers. Cell. 2012;149:994–1007.
Gerlinger M, Rowan AJ, Stuart Horswell MM, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing marco. N. Engl J Med. 2012;366:883–92.
Harbst K, Lauss M, Cirenajwis H, Isaksson K, Rosengren F, Törngren T, et al. Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma. Cancer Res. 2016;76:4765–74.
Kim TM, Jung SH, An CH, Lee SHSH, Baek IP, Kim MS. et al. Subclonal genomic architectures of primary and metastatic colorectal cancer based on intratumoral genetic heterogeneity. Clin Cancer Res. 2015;21:4461–72.
Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet. 2014;46:225–33.
Sottoriva A, Spiteri I, Piccirillo SGM, Touloumis A, Collins VP, Marioni JC, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA. 2013;110:4009–14.
de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346:251–6.
Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature. 2011;469:356–61.
Xue R, Li R, Guo H, Guo L, Su Z, Ni X, et al. Variable intra-tumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Gastroenterology. 2016;150:998–1008.
Hughes AEO, Magrini V, Demeter R, Miller CA, Fulton R, Fulton LL et al. Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing. PLoS Genet. 2014;10. https://doi.org/10.1371/journal.pgen.1004462.
Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, et al. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015;47:209–16.
Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–77.
Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40.
Hicks J, Krasnitz A, Lakshmi B, Navin NE, Riggs M, Leibu E, et al. Novel patterns of genome rearrangement and their association with survival in breast cancer. Genome Res. 2006;16:1465–79.
Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013;154:61–74.
Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell. 2010;141:583–94.
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.
Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F, et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med. 2016;22:792–9.
Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138:822–9.
Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–91.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.
Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA. 2011;108:7950–5.
Notta F, Mullighan CG, Wang JCY, Poeppl A, Doulatov S, Phillips LA, et al. Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells. Nature. 2011;469:362–7.
Visvader JE. Cells of origin in cancer. Nature. 2011;469:314–22.
Cozzio A, Passegué E, Cleary ML, Weissman IL. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 2003;17:3029–35.
Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, et al. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell. 2009;15:135–47.
Barrett LE, Granot Z, Coker C, Iavarone A, Hambardzumyan D, Holland EC, et al. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell. 2012;21:11–24.
Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A. Tumor growth need not be driven by rare cancer stem cells. Science. 2007;317:337.
Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013;152:25–38.
Hong D, Gupta R, Ancliff P, Atzberger A, Brown J, Soneji S, et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science. 2008;319:336–9.
Maenhaut C, Dumont JE, Roger PP, van Staveren WCG. Cancer stem cells: a reality, a myth, a fuzzy concept or a misnomer? An analysis. Carcinogenesis. 2010;31:149–58.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.
Blazek ER, Foutch JL, Maki G. Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys. 2007;67:1–5.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.
Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458:780–3.
Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1:389–402.
Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res. 2005;65:6207–19.
Wulf GG, Wang RY, Kuehnle I, Weidner D, Marini F, Brenner MK, et al. A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia. Blood. 2001;98:1166–73.
Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ, et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N. Engl J Med. 2010;363:1025–37.
Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146:633–44.
Ischenko I, Zhi J, Moll UM, Nemajerova A, Petrenko O. Direct reprogramming by oncogenic Ras and Myc. Proc Natl Acad Sci USA. 2013;110:3937–42.
Oshimori N, Oristian D, Fuchs E. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015;160:963–76.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.
Bapat SA, Koppikar CB, Kurrey NK. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 2005;65:3025–9.
O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.
Schepers AG, Snippert HJ, Stange DE, Born M, van den, Es JH, van, Wetering Mvande, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337:730–5.
Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis. Nature. 2012;488:527–30.
Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522–6.
Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl J Med. 2004;351:657–67.
Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178:835–49.
Van Keymeulen A, Lee MY, Ousset M, Brohée S, Rorive S, Giraddi RR, et al. Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature. 2015;525:119–23.
Ge Y, Gomez NC, Adam RC, Nikolova M, Yang H, Verma A, et al. Stem cell lineage infidelity drives wound repair and cancer. Cell. 2017;169:636–42.e14.
Yang Y, Wang G, Zhu D, Huang Y, Luo Y, Su P, et al. Epithelial-mesenchymal transition and cancer stem cell-like phenotype induced by Twist1 contribute to acquired resistance to irinotecan in colon cancer. Int J Oncol. 2017;51:515–24.
Bai F, Chan HL, Scott A, Smith MD, Fan C, Herschkowitz JI, et al. BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development. Cancer Res. 2014;74:6161–72.
Lapouge G, Beck B, Nassar D, Dubois C, Dekoninck S, Blanpain C. Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness. EMBO J. 2012;31:4563–75.
Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature. 2008;456:593–8.
Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010;466:133–7.
Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, et al. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell. 2010;17:362–75.
Taussig DC, Vargaftig J, Miraki-moud F, Griessinger E, Sharrock K, Gribben JG, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34- fraction. Blood. 2010;115:1976–85.
Piccirillo SGM, Colman S, Potter NE, Van Delft FW, Lillis S, Carnicer MJ, et al. Genetic and functional diversity of propagating cells in glioblastoma. Stem Cell Rep. 2015;4:7–15.
Giessler KM, Kleinheinz K, Huebschmann D, Balasubramanian GP, Dubash TD, Dieter SM, et al. Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer. J Exp Med. 2017;214:2073–88.
Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia. 2014;28:384–90.
Schober M, Fuchs E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci USA. 2011;108:10544–9.
Jacoby MA, Duncavage EJ, Chang GS, Miller CA, Shao J, Elliott K, et al. Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight. 2018;3:1–12.
Wong TN, Miller CA, Jotte MRM, Bagegni N, Baty JD, Schmidt AP, et al. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun. 2018;9:1–10.
Engle EK, Fisher DAC, Miller CA, McLellan MD, Fulton RS, Moore DM, et al. Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia. Leukemia. 2015;29:869–76.
Miller CA, White BS, Dees ND, Griffith M, Welch JS, Griffith OL, et al. SciClone: inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution. PLoS Comput Biol. 2014;10. https://doi.org/10.1371/journal.pcbi.1003665.
Xu J, Nuno K, Litzenburger UM, Qi Y, Corces MR, Majeti R, et al. Single-cell lineage tracing by endogenous mutations enriched in transposase accessible mitochondrial DNA. Elife. 2019;8:1–14.
Klco JM, Spencer DH, Miller CA, Griffith M, Lamprecht TL, O’Laughlin M, et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014;25:379–92.
Corces MR, Chang HY, Majeti R. Preleukemic hematopoietic stem cells in human acute myeloid leukemia. Front Oncol. 2017;7:1–8.
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.
Egan JB, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120:1060–6.
Kreso A, O’Brien C, van Galen P, Gan O, Notta F, Brown A, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal. Cancer Sci. 2013;339:543–8.
Dieter SM, Ball CR, Hoffmann CM, Nowrouzi A, Herbst F, Zavidij O, et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell. 2011;9:357–65.
Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017;355:1–11.
Weng Q, Wang J, Wang J, He D, Cheng Z, Zhang F et al. Single-cell transcriptomics uncovers glial progenitor diversity and cell fate determinants during development and gliomagenesis. Cell Stem Cell. 2019;24:707–23.
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.
Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.
Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7:651–8.
Shalapour S, Karin M, Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Investig. 2015;125:3347–55.
Shi Y, Ping YF, Zhou W, He ZC, Chen C, Bian BSJ, et al. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat Commun. 2017;8:1–17.
Lu H, Clauser KR, Tam WL, Fröse J, Ye X, Eaton EN, et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014;16:1105–17.
Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci USA. 2011;108:12425–30.
Wei J, Barr J, Kong L-Y, Wang Y, Wu A, Sharma AK, et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther. 2010;9:67–78.
You Y, Li Y, Li M, Lei M, Wu M, Qu Y, et al. Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells. Clin Exp Immunol. 2018;191:60–73.
Volonte A, Di Tomaso T, Spinelli M, Todaro M, Sanvito F, Albarello L, et al. Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol. 2014;192:523–32.
van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.
Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol. 2014;16:889–901.
Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013;210:2851–72.
Vermeulen L, De Sousa E, Melo F, van der Heijden M, Cameron K, de Jong JH, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.
Medyouf H, Mossner M, Jann JC, Nolte F, Raffel S, Herrmann C, et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell. 2014;14:824–37.
Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11:69–82.
Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell. 2010;6:141–52.
Jeon HM, Kim SH, Jin X, Park JB, Kim SH, Joshi K, et al. Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression. Cancer Res. 2014;74:4482–92.
Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153:139–52.
Kurtova AV, Xiao J, Mo Q, Pazhanisamy S, Krasnow R, Lerner SP, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature. 2014;517:209–13.
Kim SY, Hong SH, Basse PH, Wu C, Bartlett DL, Kwon YT, et al. Cancer stem cells protect non-stem cells from anoikis: Bystander effects. J Cell Biochem. 2016;13:2289–301.
Auffinger B, Tobias AL, Han Y, Lee G, Guo D, Dey M, et al. Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ. 2014;21:1119–31.
Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30:833–44.
Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573:539–45.
Venkataramani V, Tanev DI, Strahle C, Studier-fischer A, Fankhauser L, Kessler T, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019;573:532–8.
Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019;573:526–31.
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703–7.
Liberti MV, Locasale JW. The Warburg Effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41:211–8.
Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Investig. 2008;118:3930–42.
McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017;49:367–76.
Sancho P, Burgos-Ramos E, Tavera A, Bou Kheir T, Jagust P, Schoenhals M, et al. MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab. 2015;22:590–605.
Vlashi E, Lagadec C, Vergnes L, Reue K, Frohnen P, Chan M, et al. Metabolic differences in breast cancer stem cells and differentiated progeny. Breast Cancer Res Treat. 2014;146:525–34.
De Luca A, Fiorillo M, Peiris-Pagès M, Ozsvari B, Smith DL, Sanchez-Alvarez R, et al. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget. 2015;6:14777–95.
Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514:628–32.
Lee K, Giltnane JM, Balko JM, Rathmell JC, Fesik SW, Arteaga CL, et al. MYC and MCL1 cooperatively promote chemotherapy- resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26:633–47.
Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP, Sotgia F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 2014;5:11029–37.
Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci USA. 2011;108:16062–7.
Denise C, Paoli P, Calvani M, Taddei ML, Giannoni E, Kopetz S, et al. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget 2015;6. https://doi.org/10.18632/oncotarget.5991.
Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41.
Ye H, Adane B, Khan N, Stranahan AW, Park CY, Jordan CT, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche article leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Stem Cell. 2016;19:23–37.
Liu X, Li F, Huang Q, Zhang Z, Zhou L, Deng Y, et al. Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells. Cell Res. 2017;27:764–83.
Liu K, Lee J, Kim JY, Wang L, Tian Y, Chan ST, et al. Mitophagy controls the activities of tumor suppressor p53 to regulate hepatic cancer stem cells. Mol Cell. 2017;68:281–92.e5.
Yan C, Luo L, Guo CY, Goto S, Urata Y, Shao JH, et al. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett. 2017;388:34–42.
Pagotto A, Pilotto G, Mazzoldi EL, Nicoletto MO, Frezzini S, Pastò A, et al. Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. Cell Death Dis Dis. 2017;8:1–10.
Rycaj K, Tang DG. Cell-of-origin of cancer versus cancer stem cells: assays and interpretations. Cancer Res. 2015;75:4003–11.
Taussig DC, Miraki-moud F, Anjos-afonso F, Pearce DJ, Allen K, Ridler C, et al. Anti-CD38 antibody mediated clearance of human repopulating cells masks the heterogeneity of leukemia initiating cells. Blood. 2008;112:568–76.
Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM, et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell. 2010;18:510–23.
Stewart JM, Shaw PA, Gedye C, Bernardini MQ, Neel BG, Ailles LE. Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells. Proc Natl Acad Sci. 2011;108:6468–73.
Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9:391–403.
Ledur PF, Liu C, He H, Harris AR, Minussi DC, Zhou HY, et al. Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells. Neuro Oncol. 2016;18:1413–24.
Ledur PF, Onzi GR, Zong H, Lenz G. Culture conditions defining glioblastoma cells behavior: what is the impact for novel discoveries? Oncotarget. 2017;8:69185–97.
McClellan JS, Dove C, Gentles AJ, Ryan CE, Majeti R. Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages. Proc Natl Acad Sci USA. 2015;112:4074–9.
Quek L, David MD, Kennedy A, Metzner M, Amatangelo M, Shih A, et al. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med. 2018;24:1167–77.
Shih AH, Jiang Y, Meydan C, Shank K, Pandey S, Barreyro L, et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell. 2015;27:502–15.
Park SM, Gönen M, Vu L, Minuesa G, Tivnan P, Barlowe TS, et al. Musashi2 sustains the mixed-lineage leukemia’driven stem cell regulatory program. J Clin Investig. 2015;125:1286–98.
Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, et al. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell. 2015;17:675–88.
Sun Y, Zhou B, Mao F, Xu J, Miao H, Zou Z, et al. HOXA9 reprograms the enhancer landscape to promote leukemogenesis. Cancer Cell. 2018;34:643–58.e5.
Trissal MC, Wong TN, Yao JC, Ramaswamy R, Kuo I, Baty J, et al. MIR142 loss-of-function mutations derepress ASH1L to increase HOXA gene expression and promote leukemogenesis. Cancer Res. 2018;78:3510–21.
Schapiro D, Jackson HW, Raghuraman S, Fischer JR, Zanotelli VRT, Schulz D, et al. HistoCAT: Analysis of cell phenotypes and interactions in multiplex image cytometry data. Nat Methods. 2017;14:873–6.
Giesen C, Wang HAO, Schapiro D, Zivanovic N, Jacobs A, Hattendorf B, et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods. 2014;11:417–22.
Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15:501–13.
Wang Y, Liu Y, Malek SN, Zheng P, Liu Y. Targeting HIF1α eliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011;8:399–411.
Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–74.
Krause DS, Lazarides K, von Andrian UH, Van Etten RA. Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells. Nat Med. 2006;12:1175–80.
Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.
Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462:475–87.
Lu R, Wang P, Parton T, Zhou Y, Chrysovergis K, Rockowitz S, et al. Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell. 2016;30:92–107.
Acknowledgements
ATV was supported by the Philip Majerus Fellowship Fund. LFZB is supported by the NHLBI (4R00HL114732; 1R01HL137793) and grants from the V Foundation for Cancer Research, the Edward Mallinckrodt Jr. Foundation, the AA&MDS International Foundation, the CONCERN Foundation, the Department of Defense Bone Marrow Failure Research Program (BM160054) and the American Cancer Society. We thank Sapiens Scientific Illustrations for the artistic work on Figs. 1–3.
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Vessoni, A.T., Filippi-Chiela, E.C., Lenz, G. et al. Tumor propagating cells: drivers of tumor plasticity, heterogeneity, and recurrence. Oncogene 39, 2055–2068 (2020). https://doi.org/10.1038/s41388-019-1128-4
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DOI: https://doi.org/10.1038/s41388-019-1128-4
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