Metastatic tumor cells – genotypes and phenotypes

Abstract

BACKGROUND: Metastasis is the primary cause of mortality in cancer patients. Therefore, elucidating the genetics and epigenetics of metastatic tumor cells and the mechanisms by which tumor cells acquire metastatic properties constitute significant challenges in cancer research.

OBJECTIVE: To summarize the current understandings of the specific genotype and phenotype of the metastatic tumor cells.

METHOD and RESULT: In-depth genetic analysis of tumor cells, especially with advances in the next-generation sequencing, have revealed insights of the genotypes of metastatic tumor cells. Also, studies have shown that the cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) phenotypes are associated with the metastatic cascade.

CONCLUSION: In this review, we will discuss recent advances in the field by focusing on the genomic instability and phenotypic dynamics of metastatic tumor cells.

Keywords

metastasis / epithelial to mesenchymal transition (EMT) / cancer stem cell / circulating tumor cells / cellular plasticity / phenotype dynamics

References

[1] Aceto N, Bardia A, Miyamoto D T, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H(2014). Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell, 158:1110–1122

[2] Al-Hajj M, Wicha M S, Benito-Hernandez A, Morrison S J, Clarke M F (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 100:3983–3988

[3] Boral D, Vishnoi M, Liu H N, Yin W, Sprouse M L, Scamardo A, Hong D S, Tan T Z, Thiery J P, Chang J C (2017). Molecular characterization of breast cancer CTCs associated with brain metastasis. Nat Commun, 8:196

[4] Bos PD, Zhang X H F, Nadal C, Shu W, Gomis R R, Nguyen D X, Minn A J, Van de Vijver M, Gerald W, Foekens J A, Massagué J( 2009). Genes that mediate breast cancer metastasis to the brain. Nature, 459:1005–1009

[5] Brabletz T 2012. To differentiate or not–routes towards metastasis. In: Nat Rev Cancer. England. p. 425–436.

[6] Brastianos P K, Carter S L, Santagata S, Cahill D P, Taylor-Weiner A, Jones R T, Van Allen E M, Lawrence M S, Horowitz P M, Cibulskis K (2015). Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov, 5:1164–1177

[7] Cabrera M C, Hollingsworth R E, Hurt E M (2015). Cancer stem cell plasticity and tumor hierarchy. World J Stem Cells, 7:27–36

[8] Campbell P J, Yachida S, Mudie L J, Stephens P J, Pleasance E D, Stebbings L A, Morsberger L A, Latimer C, McLaren S, Lin M L (2010). The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature, 467:1109–1113

[9] Carmody L, Germain A, Morgan B, VerPlank L, Fernandez C, Forbeck E, Ting A, Feng Y, Perez J, Dandapani S (2010). Identification of a Selective Small-Molecule Inhibitor of Breast Cancer Stem Cells- Probe 1. In: Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD): National Center for Biotechnology Information (US).

[10] Chaffer C L, Marjanovic N D, Lee T, Bell G, Kleer C G, Reinhardt F, D'Alessio A C, Young R A, Weinberg R A (2013). Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell, 154:61–74

[11] Chen D, Wu M, Li Y, Chang I, Yuan Q, Ekimyan-Salvo M, Deng P, Yu B, Yu Y, Dong J (2017). Targeting BMI1(+) Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. Cell Stem Cell, 20:621–634

[12] Chiou SH, Risca VI, Wang GX, Yang D, Gruner BM, Kathiria AS, Ma RK, Vaka D, Chu P, Kozak M (2017). BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer. Cancer Discov, 7:1184–1199

[13] Chuang C H, Greenside P G, Rogers Z N, Brady J J, Yang D, Ma R K, Caswell D R, Chiou S H, Winters A F, Gruner B M (2017). Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 23:291–300

[14] Chui M H (2013). Insights into cancer metastasis from a clinicopathologic perspective: Epithelial-Mesenchymal Transition is not a necessary step. Int J Cancer, 132:1487–1495

[15] Davis F M, Stewart T A, Thompson E W, Monteith G R (2014). Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci, 35: 479–488

[16] de Sousa e Melo F, Kurtova A V, Harnoss J M, Kljavin N, Hoeck J D, Hung J, Anderson J E, Storm E E, Modrusan Z, Koeppen H (2017). A distinct role for Lgr5(+) stem cells in primary and metastatic colon cancer. Nature, 543:676–680

[17] Dragu D L, Necula L G, Bleotu C, Diaconu C C, Chivu-Economescu M (2015). Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells, 7:1185–1201

[18] DuPage M, Dooley A L, Jacks T (2009). Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc, 4(7): 1064–1072

[19] Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J (2015). Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. Nov 26;527:472–476. Epub 2015/11/13.

[20] Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson A G, Johnson A R, Lichtenberg T M, Murray B A, Ghayee H K, Else T(2017). Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell, 31:181–193

[21] Fraser M, Sabelnykova V Y, Yamaguchi T N, Heisler L E, Livingstone J, Huang V, Shiah Y J, Yousif F, Lin X, Masella A P(2017). Genomic hallmarks of localized, non-indolent prostate cancer. Nature, 541: 359–364

[22] George J T, Jolly M K, Xu S, Somarelli J A, Levine H (2017). Survival Outcomes in Cancer Patients Predicted by a Partial EMT Gene Expression Scoring Metric. Cancer Res, 77: 6415–6428

[23] Giannelli G, Villa E, Lahn M (2014). Transforming growth factor-beta as a therapeutic target in hepatocellular carcinoma. Cancer Res, 74:1890–1894

[24] Goossens N, Hoshida Y, Aguirre-Ghiso J A(2015). Origin and interpretation of cancer transcriptome profiling: the essential role of the stroma in determining prognosis and drug resistance. EMBO Mol Med, 7:1385–1387

[25] Grigore A D, Jolly M K, Jia D, Farach-Carson M C, Levine H (2016). Tumor Budding: The Name is EMT. Partial EMT. J Clin Med, 29:5

[26] Gupta P B, Chaffer C L, Weinberg R A (2009). Cancer stem cells: mirage or reality? Nat Med, 15:1010–1012

[27] Gupta P B, Onder T T, Jiang G, Tao K, Kuperwasser C, Weinberg R A, Lander E S (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138:645–659

[28] Hecht I, Natan S, Zaritsky A, Levine H, Tsarfaty I, Ben-Jacob E(2015). The motility-proliferation-metabolism interplay during metastatic invasion. Sci Rep, 5:13538

[29] Hoadley K A, Siegel M B, Kanchi K L, Miller C A, Ding L, Zhao W, He X, Parker J S, Wendl M C, Fulton R S(2016). Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases. PLoS Med, e1002174

[30] Jaggupilli A, Elkord E (2012). Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity. Clin Dev Immunol, 2012: 708036

[31] Kalluri R, Weinberg R A (2009). The basics of epithelial-mesenchymal transition. J Clin Invest, 119:1420–1428

[32] Kang Y, Siegel P M, Shu W, Drobnjak M, Kakonen S M, Cordon-Cardo C, Guise T A, Massague J (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3:537–549

[33] Ku S Y, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich Z W, Goodrich M M, Labbe D P, Gomez E C, Wang J, Long H W, Xu B, Brown M, Loda M, Sawyers C L, Ellis L, Goodrich D W (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science, 355:78–83

[34] Labib M, Mohamadi R M, Poudineh M, Ahmed S U, Ivanov I, Huang C L, Moosavi M, Sargent E H, Kelley S O (2018). Single-cell mRNA cytometry via sequence-specific nanoparticle clustering and trapping. Nat Chem, 10:489–495

[35] Lambert A W, Pattabiraman D R, Weinberg R A (2017). Emerging Biological Principles of Metastasis. Cell, 168:670–691

[36] Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri M A, Dick J E (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 367:645–648

[37] Lawson D A, Bhakta N R, Kessenbrock K, Prummel K D, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang C Y, Yaswen P, Goga A, Werb Z (2015). Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature, 526:131–135

[38] Lim J, Thiery J P 2012. Epithelial-mesenchymal transitions: insights from development. In: Development. England. p. 3471–3486.

[39] Liu H, Patel M R, Prescher J A, Patsialou A, Qian D, Lin J, Wen S, Chang Y F, Bachmann M H, Shimono Y, Dalerba P, Adorno M, Lobo N, Bueno J, Dirbas F M, Goswami S, Somlo G, Condeelis J, Contag C H, Gambhir S S, Clarke M F (2010). Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A, 107:18115–18120

[40] Liu Y, Cao X (2016). Characteristics and Significance of the Pre-metastatic Niche. Cancer Cell, 30:668–681

[41] Luzzi K J, MacDonald I C, Schmidt E E, Kerkvliet N, Morris V L, Chambers A F, Groom A C (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

[42] Magnani L, Frige G, Gadaleta R M, Corleone G, Fabris S, Kempe H, Verschure P J, Barozzi I, Vircillo V, Hong S P, Perone Y, Saini M, Trumpp A, Viale G, Neri A, Ali S, Colleoni M A, Pruneri G, Minucci S (2017). Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERalpha metastatic breast cancer. Nat Genet,49:444–450

[43] Makohon-Moore A, Iacobuzio-Donahue C A (2016). Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer,16:553–565

[44] Makohon-Moore A P, Zhang M, Reiter J G, Bozic I, Allen B, Kundu D, Chatterjee K, Wong F, Jiao Y, Kohutek Z A, Hong J, Attiyeh M, Javier B, Wood L D, Hruban R H, Nowak M A, Papadopoulos N, Kinzler K W, Vogelstein B, Iacobuzio-Donahue C A (2017). Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet, 49:358–366

[45] Mani S A, Guo W, Liao M J, Eaton E N, Ayyanan A, Zhou A Y, Brooks M, Reinhard F, Zhang C C, Shipitsin M, Campbell L L, Polyak K, Brisken C, Yang J, Weinberg R A (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133:704–715

[46] Martinez-Cardus A, Moran S, Musulen E, Moutinho C, Manzano J L, Martinez-Balibrea E, Tierno M, Elez E, Landolfi S, Lorden P, Arribas C, Müller F, Bock C, Tabernero J, Esteller M (2016). Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer. Gastroenterology, 151:961–972

[47] McCauley HA, Chevrier V, Birnbaum D, Guasch G (2017). De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGFbeta-deficient squamous cell carcinoma from transition zones. Elife, 21:6

[48] McDonald O G, Li X, Saunders T, Tryggvadottir R, Mentch S J, Warmoes M O, Word A E, Carrer A, Salz T H, Natsume S, Stauffer K M, Makohon-Moore A, Zhong Y, Wu H, Wellen K E, Locasale J W, Iacobuzio-Donahue C A, Feinberg A P (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet, 49:367–376

[49] Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massagué J ( 2005). Genes that mediate breast cancer metastasis to lung. Nature, 436:518–524.

[50] Nagare R P, Sneha S, Priya S K, Ganesan T S (2017). Cancer Stem Cells- Are Surface Markers Alone Sufficient? Curr Stem Cell Res Ther, 12(1): 37–44

[51] Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie W R, Hicks J, Wigler M (2011). Tumour evolution inferred by single-cell sequencing. Nature, 472:90–94

[52] Navin N E (2015). The first five years of single-cell cancer genomics and beyond. Genome Res, 25:1499–1507

[53] Nguyen D X, Massague J (2007). Genetic determinants of cancer metastasis. Nat Rev Genet, 8:341–352

[54] Olsen S N, Wronski A, Castano Z, Dake B, Malone C, De Raedt T, Enos M, DeRose YS, Zhou W, Guerra S, Loda M, Welm A, Partridge A H, McAllister S S, Kuperwasser C, Cichowski K (2017). Loss of RasGAP tumor suppressors underlies the aggressive nature of luminal b breast cancers. Cancer Discov, 7:202–217

[55] Patel A P, Tirosh I, Trombetta J J, Shalek A K, Gillespie S M, Wakimoto H, Cahill D P, Nahed B V, Curry W T, Martuza R L, Louis D N, Rozenblatt-Rosen O, Suvà M L, Regev A, Bernstein B E (2014). Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science, 344:1396–1401

[56] Patel S A, Vanharanta S (2016). Epigenetic determinants of metastasis. Mol Oncol, 11(1): 79–96

[57] Peitzsch C, Tyutyunnykova A, Pantel K, Dubrovska A (2017). Cancer stem cells: The root of tumor recurrence and metastases. Semin Cancer Biol, 44(Feb): 10–24

[58] Pon J R, Marra M A (2015). Driver and passenger mutations in cancer. Annu Rev Pathol, 10(1): 25–50

[59] Poudineh M, Aldridge P M, Ahmed S, Green B J, Kermanshah L, Nguyen V, Tu C, Mohamadi R M, Nam R K, Hansen A (2017). Tracking the dynamics of circulating tumour cell phenotypes using nanoparticle-mediated magnetic ranking. Nat Nanotechnol, 12:274–281

[60] Puram S V, Tirosh I, Parikh A S, Patel A P, Yizhak K, Gillespie S, Rodman C, Luo C L, Mroz E A, Emerick K S (2017). Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell, 171:1611–1624

[61] Rinaldi L, Avgustinova A, Martin M, Datta D, Solanas G, Prats N, Benitah S A (2017). Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-gamma. Elife, 20:6

[62] Robinson D R, Wu Y M, Lonigro R J, Vats P, Cobain E, Everett J, Cao X, Rabban E, Kumar-Sinha C, Raymond V (2017). Integrative clinical genomics of metastatic cancer. Nature, 548: 297–303

[63] Rodon J, Carducci M A, Sepulveda-Sanchez J M, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly A L(2015). First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res, 21:553–560

[64] Roe J S, Hwang C I, Somerville T D D, Milazzo J P, Lee E J, Da Silva B, Maiorino L, Tiriac H, Young C M, Miyabayashi K (2017). Enhancer reprogramming promotes pancreatic cancer metastasis. Cell, 170:875–888

[65] Shackleton M, Quintana E, Fearon E R, Morrison S J (2009). Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell, 138:822–829

[66] Sheffield N C, Pierron G, Klughammer J, Datlinger P, Schonegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E (2017). DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat Med, 23:386–395

[67] Sinkala E, Sollier-Christen E, Renier C, Rosas-Canyelles E, Che J, Heirich K, Duncombe T A, Vlassakis J, Yamauchi K A, Huang H ( 2017) . Profiling protein expression in circulating tumour cells using microfluidic western blotting. Nat Commun, 8:14622

[68] Tan TZ, Miow Q H, Miki Y, Noda T, Mori S, Huang R Y, Thiery J P (2014). Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med, 6:1279–1293

[69] Thiery J P, Acloque H, Huang R Y, Nieto M A (2009). Epithelial-mesenchymal transitions in development and disease. In: Cell. United States. p. 871–890.

[70] Tran H D, Luitel K, Kim M, Zhang K, Longmore G D, Tran D D (2014). Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. Cancer Res, 74:6330–6340

[71] Tsai J H, Donaher J L, Murphy D A, Chau S, Yang J (2012). Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell, 22:725–736

[72] Valastyan S, Weinberg R A (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell, 147:275–292

[73] Wishart D S (2015). Is Cancer a Genetic Disease or a Metabolic Disease? In: EBioMedicine. p. 478–479.

[74] Yates L R, Knappskog S, Wedge D, Farmery J H R, Gonzalez S, Martincorena I, Alexandrov L B, Van Loo P, Haugland H K, Lilleng P K, ( 2017). Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell, 32:169–184.e167

[75] Ye X, Brabletz T, Kang Y, Longmore G D, Nieto M A, Stanger B Z, Yang J, Weinberg R A (2017). Upholding a role for EMT in breast cancer metastasis. Nature, 547:E1–e3

[76] Ye X, Tam W L, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, Weinberg R A (2015). Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature, 525: 256–260. Epub 2015/09/04.

[77] Yeung KT, Yang J. 2017. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol, 11:28–39

[78] Yu M, Bardia A, Wittner B S, Stott S L, Smas M E, Ting D T, Isakoff S J, Ciciliano J C, Wells M N, Shah A M (2013). Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science, 339:580–584

[79] Zehir A, Benayed R, Shah R H, Syed A, Middha S, Kim H R, Srinivasan P, Gao J, Chakravarty D, Devlin SM (2017). Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med, 23:703–713

[80] Zheng X, Carstens J L, Kim J, Scheible M, Kaye J, Sugimoto H, Wu C C, LeBleu V S, Kalluri R (2015). Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature, 527:525–530

[81] Zhu S, Zhang X, Weichert-Leahey N, Dong Z, Zhang C, Lopez G, Tao T, He S, Wood A C, Oldridge D (2017). LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. Cancer Cell, 32:310–323.e315

Compliance with ethics guidelines

Authors declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature