Induced Pluripotent Stem Cells and Induced Pluripotent Cancer Cells in Cancer Disease Modeling

Zhu, Dandan; Kong, Celine Shuet Lin; Gingold, Julian A.; Zhao, Ruiying; Lee, Dung-Fang

doi:10.1007/5584_2018_257

Dandan Zhu⁷,
Celine Shuet Lin Kong⁷,
Julian A. Gingold⁸,
Ruiying Zhao⁷ &
…
Dung-Fang Lee^7,9,10,11

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1119))

1746 Accesses
12 Citations
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Abstract

In 2006, Noble Prize laureate Shinya Yamanaka discovered that a set of transcription factors can reprogram terminally differentiated somatic cells to a pluripotent stem cell state. Since then, induced pluripotent stem cells (iPSCs) have come into the public spotlight. Amidst a growing field of promising clinical uses of iPSCs in recent years, cancer disease modeling has emerged as a particularly promising and rapidly translatable application of iPSCs. Technological advances in genome editing over the past few years have facilitated increasingly rapid progress in generation of iPSCs with clearly defined genetic backgrounds to complement existing patient-derived models. Improved protocols for differentiation of iPSCs, engineered iPSCs and embryonic stem cells (ESCs) now permit the study of disease biology in the majority of somatic cell types. Here, we highlight current efforts to create patient-derived iPSC disease models to study various cancer types. We review the advantages and current challenges of using iPSCs in cancer disease modeling.

Author contributed equally with all other contributors.Dandan Zhu and Celine Shuet Lin Kong

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Abbreviations

AML:: acute myeloid leukemia
APC:: adenomatous polyposis cell
CML:: chronic myeloid leukemia
COs:: colorectal organoids
ER:: estrogen receptor
ESCs:: embryonic stem cells
FAP:: familial adenomatous polyposis
HBOC:: hereditary breast and ovarian cancer
iPCCs:: induced pluripotent cancer cells
iPSCs:: induced pluripotent stem cells
JMML:: juvenile myelomonocytic leukemia
LFS:: Li-Fraumeni syndrome
LSC:: leukemic stem cells
MDS:: Myelodysplastic syndrome
MSCs:: mesenchymal stem cells
NS:: Noonan syndrome
PDAC:: pancreatic ductal adenocarcinoma
PR:: progesterone receptor
sgRNA:: single guide RNA
TALEN:: transcription activator-like effector nuclease
ZFN:: zinc finger nuclease

References

Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260(5109):812–816
Article CAS PubMed Google Scholar
Abyzov A, Mariani J, Palejev D, Zhang Y, Haney MS, Tomasini L, Ferrandino AF, Rosenberg Belmaker LA, Szekely A, Wilson M, Kocabas A, Calixto NE, Grigorenko EL, Huttner A, Chawarska K, Weissman S, Urban AE, Gerstein M, Vaccarino FM (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492(7429):438–442. https://doi.org/10.1038/nature11629
Article CAS PubMed PubMed Central Google Scholar
An MC, Zhang N, Scott G, Montoro D, Wittkop T, Mooney S, Melov S, Ellerby LM (2012) Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11(2):253–263. https://doi.org/10.1016/j.stem.2012.04.026
Article CAS PubMed PubMed Central Google Scholar
Ang YS, Rivas RN, Ribeiro AJS, Srivas R, Rivera J, Stone NR, Pratt K, Mohamed TMA, Fu JD, Spencer CI, Tippens ND, Li M, Narasimha A, Radzinsky E, Moon-Grady AJ, Yu H, Pruitt BL, Snyder MP, Srivastava D (2016) Disease model of GATA4 mutation reveals transcription factor cooperativity in human cardiogenesis. Cell 167(7):1734–1749 e1722. https://doi.org/10.1016/j.cell.2016.11.033
Article CAS PubMed PubMed Central Google Scholar
Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y, Yang W, Gruber PJ, Epstein JA, Morrisey EE (2011) Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8(4):376–388. https://doi.org/10.1016/j.stem.2011.03.001
Article CAS PubMed PubMed Central Google Scholar
Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S (2008) Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 321(5889):699–702. https://doi.org/10.1126/science.1154884
Article CAS PubMed Google Scholar
Apostolou E, Hochedlinger K (2013) Chromatin dynamics during cellular reprogramming. Nature 502(7472):462–471. https://doi.org/10.1038/nature12749
Article CAS PubMed PubMed Central Google Scholar
Ban H, Nishishita N, Fusaki N, Tabata T, Saeki K, Shikamura M, Takada N, Inoue M, Hasegawa M, Kawamata S, Nishikawa S (2011) Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci U S A 108(34):14234–14239. https://doi.org/10.1073/pnas.1103509108
Article PubMed PubMed Central Google Scholar
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L, Network TR (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. https://doi.org/10.1016/j.cell.2013.09.034
Article CAS PubMed PubMed Central Google Scholar
Briggs JA, Sun J, Shepherd J, Ovchinnikov DA, Chung TL, Nayler SP, Kao LP, Morrow CA, Thakar NY, Soo SY, Peura T, Grimmond S, Wolvetang EJ (2013) Integration-free induced pluripotent stem cells model genetic and neural developmental features of down syndrome etiology. Stem Cells 31(3):467–478. https://doi.org/10.1002/stem.1297
Article CAS PubMed Google Scholar
Carvajal-Vergara X, Sevilla A, D’Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, Tartaglia M, Gelb BD, Lemischka IR (2010) Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465(7299):808–812. https://doi.org/10.1038/nature09005
Article CAS PubMed PubMed Central Google Scholar
Chao MP, Gentles AJ, Chatterjee S, Lan F, Reinisch A, Corces MR, Xavy S, Shen J, Haag D, Chanda S, Sinha R, Morganti RM, Nishimura T, Ameen M, Wu H, Wernig M, Wu JC, Majeti R (2017) Human AML-iPSCs reacquire leukemic properties after differentiation and model clonal variation of disease. Cell Stem Cell 20(3):329–344 e327. https://doi.org/10.1016/j.stem.2016.11.018
Article CAS PubMed PubMed Central Google Scholar
Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149(1):36–47. https://doi.org/10.1016/j.cell.2012.03.009
Article CAS PubMed PubMed Central Google Scholar
Cheng L, Hansen NF, Zhao L, Du Y, Zou C, Donovan FX, Chou BK, Zhou G, Li S, Dowey SN, Ye Z, Program NCS, Chandrasekharappa SC, Yang H, Mullikin JC, Liu PP (2012) Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell 10(3):337–344. https://doi.org/10.1016/j.stem.2012.01.005
Article CAS PubMed PubMed Central Google Scholar
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823. https://doi.org/10.1126/science.1231143
Article CAS PubMed PubMed Central Google Scholar
Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ (2011) Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 121(1):396–409. https://doi.org/10.1172/JCI35721
Article CAS PubMed Google Scholar
Crespo M, Vilar E, Tsai SY, Chang K, Amin S, Srinivasan T, Zhang T, Pipalia NH, Chen HJ, Witherspoon M, Gordillo M, Xiang JZ, Maxfield FR, Lipkin S, Evans T, Chen S (2017) Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat Med 23(7):878–884
Article CAS PubMed PubMed Central Google Scholar
De Los Angeles A, Ferrari F, Xi R, Fujiwara Y, Benvenisty N, Deng H, Hochedlinger K, Jaenisch R, Lee S, Leitch HG, Lensch MW, Lujan E, Pei D, Rossant J, Wernig M, Park PJ, Daley GQ (2015) Hallmarks of pluripotency. Nature 525(7570):469–478. https://doi.org/10.1038/nature15515
Article CAS PubMed Google Scholar
Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H, Cavaleri F, Nagano M, Drummond NJ, Taanman JW, Schapira AH, Gwinn K, Hardy J, Lewis PA, Kunath T (2011) Parkinson’s disease induced pluripotent stem cells with triplication of the alpha-synuclein locus. Nat Commun 2:440. https://doi.org/10.1038/ncomms1453
Article CAS PubMed Google Scholar
Doulatov S, Vo LT, Macari ER, Wahlster L, Kinney MA, Taylor AM, Barragan J, Gupta M, McGrath K, Lee HY, Humphries JM, Devine A, Narla A, Alter BP, Beggs AH, Agarwal S, Ebert BL, Gazda HT, Lodish HF, Sieff CA, Schlaeger TM, Zon LI, Daley GQ (2017) Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci Transl Med 9(376):eaah5645. https://doi.org/10.1126/scitranslmed.aah5645
Article CAS PubMed PubMed Central Google Scholar
Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, Investigators I (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417. https://doi.org/10.1056/NEJMoa062867
Article CAS PubMed Google Scholar
Funato K, Major T, Lewis PW, Allis CD, Tabar V (2014) Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346(6216):1529–1533. https://doi.org/10.1126/science.1253799
Article CAS PubMed PubMed Central Google Scholar
Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85(8):348–362
Article CAS PubMed PubMed Central Google Scholar
Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182):120–122
Article CAS PubMed Google Scholar
Gingold J, Zhou R, Lemischka IR, Lee DF (2016) Modeling Cancer with pluripotent stem cells. Trends Cancer 2(9):485–494. https://doi.org/10.1016/j.trecan.2016.07.007
Article PubMed PubMed Central Google Scholar
Gordge PC, Hulme MJ, Clegg RA, Miller WR (1996) Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue. Eur J Cancer 32A(12):2120–2126
Article CAS PubMed Google Scholar
Guenther MG, Frampton GM, Soldner F, Hockemeyer D, Mitalipova M, Jaenisch R, Young RA (2010) Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7(2):249–257. https://doi.org/10.1016/j.stem.2010.06.015
Article CAS PubMed PubMed Central Google Scholar
Guha P, Morgan JW, Mostoslavsky G, Rodrigues NP, Boyd AS (2017) Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 21(1):144–148. https://doi.org/10.1016/j.stem.2017.03.012
Article CAS PubMed Google Scholar
Hockemeyer D, Jaenisch R (2016) Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18(5):573–586. https://doi.org/10.1016/j.stem.2016.04.013
Article CAS PubMed PubMed Central Google Scholar
Hu K, Yu J, Suknuntha K, Tian S, Montgomery K, Choi KD, Stewart R, Thomson JA, Slukvin II (2011) Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117(14):e109–e119. https://doi.org/10.1182/blood-2010-07-298331
Article CAS PubMed PubMed Central Google Scholar
Hussein SM, Batada NN, Vuoristo S, Ching RW, Autio R, Narva E, Ng S, Sourour M, Hamalainen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz M, Brustle O, Bazett-Jones DP, Alitalo K, Lahesmaa R, Nagy A, Otonkoski T (2011) Copy number variation and selection during reprogramming to pluripotency. Nature 471(7336):58–62. https://doi.org/10.1038/nature09871
Article CAS PubMed Google Scholar
Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482(7384):216–220. https://doi.org/10.1038/nature10821
Article CAS PubMed PubMed Central Google Scholar
Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A, Feldman O, Gepstein A, Arbel G, Hammerman H, Boulos M, Gepstein L (2011) Modelling the long QT syndrome with induced pluripotent stem cells. Nature 471(7337):225–229. https://doi.org/10.1038/nature09747
Article CAS PubMed Google Scholar
Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458(7239):771–775. https://doi.org/10.1038/nature07864
Article CAS PubMed PubMed Central Google Scholar
Karakikes I, Termglinchan V, Wu JC (2014) Human-induced pluripotent stem cell models of inherited cardiomyopathies. Curr Opin Cardiol 29(3):214–219. https://doi.org/10.1097/HCO.0000000000000049
Article PubMed PubMed Central Google Scholar
Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4(6):472–476. https://doi.org/10.1016/j.stem.2009.05.005
Article CAS PubMed PubMed Central Google Scholar
Kim J, Hoffman JP, Alpaugh RK, Rhim AD, Reichert M, Stanger BZ, Furth EE, Sepulveda AR, Yuan CX, Won KJ, Donahue G, Sands J, Gumbs AA, Zaret KS (2013) An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep 3(6):2088–2099. https://doi.org/10.1016/j.celrep.2013.05.036
Article CAS PubMed PubMed Central Google Scholar
Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein WL, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12(4):487–496. https://doi.org/10.1016/j.stem.2013.01.009
Article CAS PubMed Google Scholar
Kooreman NG, Kim Y, de Almeida PE, Termglinchan V, Diecke S, Shao NY, Wei TT, Yi H, Dey D, Nelakanti R, Brouwer TP, Paik DT, Sagiv-Barfi I, Han A, Quax PHA, Hamming JF, Levy R, Davis MM, Wu JC (2018) Autologous iPSC-based vaccines elicit anti-tumor responses in vivo. Cell Stem Cell 22(4):501–513 e507. https://doi.org/10.1016/j.stem.2018.01.016
Article CAS PubMed PubMed Central Google Scholar
Kotini AG, Chang CJ, Boussaad I, Delrow JJ, Dolezal EK, Nagulapally AB, Perna F, Fishbein GA, Klimek VM, Hawkins RD, Huangfu D, Murry CE, Graubert T, Nimer SD, Papapetrou EP (2015) Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat Biotechnol 33(6):646–655. https://doi.org/10.1038/nbt.3178
Article CAS PubMed PubMed Central Google Scholar
Kotini AG, Chang CJ, Chow A, Yuan H, Ho TC, Wang T, Vora S, Solovyov A, Husser C, Olszewska M, Teruya-Feldstein J, Perumal D, Klimek VM, Spyridonidis A, Rampal RK, Silverman L, Reddy EP, Papaemmanuil E, Parekh S, Greenbaum BD, Leslie CS, Kharas MG, Papapetrou EP (2017) Stage-specific human induced pluripotent stem cells map the progression of myeloid transformation to transplantable leukemia. Cell Stem Cell 20(3):315–328 e317. https://doi.org/10.1016/j.stem.2017.01.009
Article CAS PubMed PubMed Central Google Scholar
Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L (2011) Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480(7378):547–551. https://doi.org/10.1038/nature10648
Article CAS PubMed PubMed Central Google Scholar
Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, Ku S, Martynova M, Semechkin R, Galat V, Gottesfeld J, Izpisua Belmonte JC, Murry C, Keirstead HS, Park HS, Schmidt U, Laslett AL, Muller FJ, Nievergelt CM, Shamir R, Loring JF (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8(1):106–118. https://doi.org/10.1016/j.stem.2010.12.003
Article CAS PubMed PubMed Central Google Scholar
Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461(7262):402–406. https://doi.org/10.1038/nature08320
Article CAS PubMed PubMed Central Google Scholar
Lee DF, Su J, Kim HS, Chang B, Papatsenko D, Zhao R, Yuan Y, Gingold J, Xia W, Darr H, Mirzayans R, Hung MC, Schaniel C, Lemischka IR (2015) Modeling familial cancer with induced pluripotent stem cells. Cell 161(2):240–254
Article CAS PubMed PubMed Central Google Scholar
Li FP, Fraumeni JF Jr (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4):747–752
Article CAS PubMed Google Scholar
Lin YH, Jewell BE, Gingold J, Lu L, Zhao R, Wang LL, Lee DF (2017) Osteosarcoma: molecular pathogenesis and iPSC modeling. Trends Mol Med 23(8):737–755. https://doi.org/10.1016/j.molmed.2017.06.004
Article CAS PubMed PubMed Central Google Scholar
Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K (2008) Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci U S A 105(8):2883–2888. https://doi.org/10.1073/pnas.0711983105
Article PubMed PubMed Central Google Scholar
Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1(1):55–70. https://doi.org/10.1016/j.stem.2007.05.014
Article CAS PubMed Google Scholar
Mali P, Chou BK, Yen J, Ye Z, Zou J, Dowey S, Brodsky RA, Ohm JE, Yu W, Baylin SB, Yusa K, Bradley A, Meyers DJ, Mukherjee C, Cole PA, Cheng L (2010) Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells 28(4):713–720. https://doi.org/10.1002/stem.402
Article CAS PubMed PubMed Central Google Scholar
Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, Watanabe T, Kanai T, Sato T (2015) Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med 21(3):256–262. https://doi.org/10.1038/nm.3802
Article CAS PubMed Google Scholar
Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, Plath K, Lowry WE, Benvenisty N (2010) Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7(4):521–531. https://doi.org/10.1016/j.stem.2010.07.017
Article CAS PubMed Google Scholar
Moad M, Pal D, Hepburn AC, Williamson SC, Wilson L, Lako M, Armstrong L, Hayward SW, Franco OE, Cates JM, Fordham SE, Przyborski S, Carr-Wilkinson J, Robson CN, Heer R (2013) A novel model of urinary tract differentiation, tissue regeneration, and disease: reprogramming human prostate and bladder cells into induced pluripotent stem cells. Eur Urol 64(5):753–761. https://doi.org/10.1016/j.eururo.2013.03.054
Article PubMed PubMed Central Google Scholar
Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L, Dorn T, Goedel A, Hohnke C, Hofmann F, Seyfarth M, Sinnecker D, Schomig A, Laugwitz KL (2010) Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363(15):1397–1409. https://doi.org/10.1056/NEJMoa0908679
Article CAS PubMed Google Scholar
Mulero-Navarro S, Sevilla A, Roman AC, Lee DF, D’Souza SL, Pardo S, Riess I, Su J, Cohen N, Schaniel C, Rodriguez NA, Baccarini A, Brown BD, Cave H, Caye A, Strullu M, Yalcin S, Park CY, Dhandapany PS, Yongchao G, Edelmann L, Bahieg S, Raynal P, Flex E, Tartaglia M, Moore KA, Lemischka IR, Gelb BD (2015) Myeloid dysregulation in a human induced pluripotent stem cell model of PTPN11-Associated juvenile myelomonocytic leukemia. Cell Rep 13(3):504–515
Article CAS PubMed PubMed Central Google Scholar
Nagase H, Miyoshi Y, Horii A, Aoki T, Ogawa M, Utsunomiya J, Baba S, Sasazuki T, Nakamura Y (1992) Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 52(14):4055–4057
CAS PubMed Google Scholar
Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101–106. https://doi.org/10.1038/nbt1374
Article CAS PubMed Google Scholar
Narsinh KH, Jia F, Robbins RC, Kay MA, Longaker MT, Wu JC (2011) Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors. Nat Protoc 6(1):78–88. https://doi.org/10.1038/nprot.2010.173
Article CAS PubMed Google Scholar
Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schule B, Dolmetsch RE, Langston W, Palmer TD, Pera RR (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8(3):267–280. https://doi.org/10.1016/j.stem.2011.01.013
Article CAS PubMed PubMed Central Google Scholar
Noonan JA (1968) Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child 116(4):373–380
Article CAS PubMed Google Scholar
Nsair A, MacLellan WR (2011) Induced pluripotent stem cells for regenerative cardiovascular therapies and biomedical discovery. Adv Drug Deliv Rev 63(4–5):324–330. https://doi.org/10.1016/j.addr.2011.01.013
Article CAS PubMed PubMed Central Google Scholar
Oishi K, Zhang H, Gault WJ, Wang CJ, Tan CC, Kim IK, Ying H, Rahman T, Pica N, Tartaglia M, Mlodzik M, Gelb BD (2009) Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development. Hum Mol Genet 18(1):193–201. https://doi.org/10.1093/hmg/ddn336
Article CAS PubMed Google Scholar
Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903):949–953. https://doi.org/10.1126/science.1164270
Article CAS PubMed Google Scholar
Papapetrou EP (2016) Patient-derived induced pluripotent stem cells in cancer research and precision oncology. Nat Med 22(12):1392–1401. https://doi.org/10.1038/nm.4238
Article CAS PubMed PubMed Central Google Scholar
Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008a) Disease-specific induced pluripotent stem cells. Cell 134(5):877–886. https://doi.org/10.1016/j.cell.2008.07.041
Article CAS PubMed PubMed Central Google Scholar
Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA, Lerou PH, Lensch MW, Daley GQ (2008b) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451(7175):141–146. https://doi.org/10.1038/nature06534
Article CAS PubMed Google Scholar
Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest 120(9):3127–3136. https://doi.org/10.1172/JCI43122
Article CAS PubMed PubMed Central Google Scholar
Raya A, Rodriguez-Piza I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castella M, Rio P, Sleep E, Gonzalez F, Tiscornia G, Garreta E, Aasen T, Veiga A, Verma IM, Surralles J, Bueren J, Izpisua Belmonte JC (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460(7251):53–59. https://doi.org/10.1038/nature08129
Article CAS PubMed PubMed Central Google Scholar
Richard JP, Maragakis NJ (2015) Induced pluripotent stem cells from ALS patients for disease modeling. Brain Res 1607:15–25. https://doi.org/10.1016/j.brainres.2014.09.017
Article CAS PubMed Google Scholar
Roberts AE, Allanson JE, Tartaglia M, Gelb BD (2013) Noonan syndrome. Lancet 381(9863):333–342. https://doi.org/10.1016/S0140-6736(12)61023-X
Article CAS PubMed PubMed Central Google Scholar
Rowley JD (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243(5405):290–293
Article CAS PubMed Google Scholar
Sancho-Martinez I, Nivet E, Xia Y, Hishida T, Aguirre A, Ocampo A, Ma L, Morey R, Krause MN, Zembrzycki A, Ansorge O, Vazquez-Ferrer E, Dubova I, Reddy P, Lam D, Hishida Y, Wu MZ, Esteban CR, O’Leary D, Wahl GM, Verma IM, Laurent LC, Izpisua Belmonte JC (2016) Establishment of human iPSC-based models for the study and targeting of glioma initiating cells. Nat Commun 7:10743. https://doi.org/10.1038/ncomms10743
Article CAS PubMed PubMed Central Google Scholar
Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, Nieuwenhuis EE, Beekman JM, Clevers H (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13(6):653–658. https://doi.org/10.1016/j.stem.2013.11.002
Article CAS PubMed Google Scholar
Seki T, Yuasa S, Oda M, Egashira T, Yae K, Kusumoto D, Nakata H, Tohyama S, Hashimoto H, Kodaira M, Okada Y, Seimiya H, Fusaki N, Hasegawa M, Fukuda K (2010) Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 7(1):11–14. https://doi.org/10.1016/j.stem.2010.06.003
Article CAS PubMed Google Scholar
Serwold T, Hochedlinger K, Inlay MA, Jaenisch R, Weissman IL (2007) Early TCR expression and aberrant T cell development in mice with endogenous prerearranged T cell receptor genes. J Immunol 179(2):928–938
Article CAS PubMed Google Scholar
Sexton AN, Regalado SG, Lai CS, Cost GJ, O’Neil CM, Urnov FD, Gregory PD, Jaenisch R, Collins K, Hockemeyer D (2014) Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev 28(17):1885–1899. https://doi.org/10.1101/gad.246819.114
Article CAS PubMed PubMed Central Google Scholar
Soldner F, Laganiere J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe LI, Myers RH, Lindquist S, Zhang L, Guschin D, Fong LK, Vu BJ, Meng X, Urnov FD, Rebar EJ, Gregory PD, Zhang HS, Jaenisch R (2011) Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146(2):318–331. https://doi.org/10.1016/j.cell.2011.06.019
Article CAS PubMed PubMed Central Google Scholar
Soyombo AA, Wu Y, Kolski L, Rios JJ, Rakheja D, Chen A, Kehler J, Hampel H, Coughran A, Ross TS (2013) Analysis of induced pluripotent stem cells from a BRCA1 mutant family. Stem Cell Rep 1(4):336–349. https://doi.org/10.1016/j.stemcr.2013.08.004
Article CAS Google Scholar
Sperling AS, Gibson CJ, Ebert BL (2017) The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer 17(1):5–19. https://doi.org/10.1038/nrc.2016.112
Article CAS PubMed Google Scholar
Stadtfeld M, Hochedlinger K (2010) Induced pluripotency: history, mechanisms, and applications. Genes Dev 24(20):2239–2263. https://doi.org/10.1101/gad.1963910
Article CAS PubMed PubMed Central Google Scholar
Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (2008) Induced pluripotent stem cells generated without viral integration. Science 322(5903):945–949. https://doi.org/10.1126/science.1162494
Article CAS PubMed PubMed Central Google Scholar
Stricker SH, Feber A, Engstrom PG, Caren H, Kurian KM, Takashima Y, Watts C, Way M, Dirks P, Bertone P, Smith A, Beck S, Pollard SM (2013) Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev 27(6):654–669. https://doi.org/10.1101/gad.212662.112
Article CAS PubMed PubMed Central Google Scholar
Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R (2011) Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biotechnol 29(5):443–448. https://doi.org/10.1038/nbt.1862
Article CAS PubMed PubMed Central Google Scholar
Suknuntha K, Ishii Y, Tao L, Hu K, McIntosh BE, Yang D, Swanson S, Stewart R, Wang JYJ, Thomson J, Slukvin I (2015) Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells. Stem Cell Res 15(3):678–693. https://doi.org/10.1016/j.scr.2015.10.015
Article CAS PubMed PubMed Central Google Scholar
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676
Article CAS PubMed Google Scholar
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872. https://doi.org/10.1016/j.cell.2007.11.019
Article CAS PubMed Google Scholar
Tu J, Huo Z, Liu M, Wang D, Xu A, Zhou R, Zhu D, Gingold J, Shen J, Zhao R, Lee DF (2018) Generation of human embryonic stem cell line with heterozygous RB1 deletion by CRIPSR/Cas9 nickase. Stem Cell Res 28:29–32. https://doi.org/10.1016/j.scr.2018.01.021
Article CAS PubMed PubMed Central Google Scholar
Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819. https://doi.org/10.1038/nrc1457
Article CAS PubMed Google Scholar
Visvader JE (2011) Cells of origin in cancer. Nature 469(7330):314–322. https://doi.org/10.1038/nature09781
Article CAS PubMed Google Scholar
Vizcardo R, Masuda K, Yamada D, Ikawa T, Shimizu K, Fujii S, Koseki H, Kawamoto H (2013) Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8(+) T cells. Cell Stem Cell 12(1):31–36. https://doi.org/10.1016/j.stem.2012.12.006
Article CAS PubMed Google Scholar
Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5):618–630. https://doi.org/10.1016/j.stem.2010.08.012
Article CAS PubMed PubMed Central Google Scholar
Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448(7151):318–324. https://doi.org/10.1038/nature05944
Article CAS PubMed Google Scholar
Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A (2009) piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458(7239):766–770. https://doi.org/10.1038/nature07863
Article CAS PubMed PubMed Central Google Scholar
Xu A, Zhou R, Tu J, Huo Z, Zhu D, Wang D, Gingold JA, Mata H, Rao PH, Liu M, Mohamed AMT, Kong CSL, Jewell BE, Xia W, Zhao R, Hung MC, Lee DF (2018) Establishment of a human embryonic stem cell line with homozygous TP53 R248W mutant by TALEN mediated gene editing. Stem Cell Res 29:215–219. https://doi.org/10.1016/j.scr.2018.04.013
Article CAS PubMed PubMed Central Google Scholar
Yamanaka S (2010) Patient-specific pluripotent stem cells become even more accessible. Cell Stem Cell 7(1):1–2. https://doi.org/10.1016/j.stem.2010.06.009
Article CAS PubMed Google Scholar
Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE (2011) Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471(7337):230–234. https://doi.org/10.1038/nature09855
Article CAS PubMed PubMed Central Google Scholar
Yi F, Liu GH, Izpisua Belmonte JC (2012) Human induced pluripotent stem cells derived hepatocytes: rising promise for disease modeling, drug development and cell therapy. Protein Cell 3(4):246–250. https://doi.org/10.1007/s13238-012-2918-4
Article CAS PubMed PubMed Central Google Scholar
Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, Depinho RA (2016) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 30(4):355–385. https://doi.org/10.1101/gad.275776.115
Article CAS PubMed PubMed Central Google Scholar
Yoshida Y, Yamanaka S (2010) Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell-based regeneration. Circulation 122(1):80–87. https://doi.org/10.1161/CIRCULATIONAHA.109.881433
Article PubMed Google Scholar
Young MA, Larson DE, Sun CW, George DR, Ding L, Miller CA, Lin L, Pawlik KM, Chen K, Fan X, Schmidt H, Kalicki-Veizer J, Cook LL, Swift GW, Demeter RT, Wendl MC, Sands MS, Mardis ER, Wilson RK, Townes TM, Ley TJ (2012) Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10(5):570–582. https://doi.org/10.1016/j.stem.2012.03.002
Article CAS PubMed PubMed Central Google Scholar
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920. https://doi.org/10.1126/science.1151526
Article CAS PubMed Google Scholar
Zhang X, Cruz FD, Terry M, Remotti F, Matushansky I (2013) Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene 32(18):2249–2260., 2260 e2241–2221. https://doi.org/10.1038/onc.2012.237
Article CAS PubMed Google Scholar
Zhao Y, Yin X, Qin H, Zhu F, Liu H, Yang W, Zhang Q, Xiang C, Hou P, Song Z, Liu Y, Yong J, Zhang P, Cai J, Liu M, Li H, Li Y, Qu X, Cui K, Zhang W, Xiang T, Wu Y, Zhao Y, Liu C, Yu C, Yuan K, Lou J, Ding M, Deng H (2008) Two supporting factors greatly improve the efficiency of human iPSC generation. Cell Stem Cell 3(5):475–479. https://doi.org/10.1016/j.stem.2008.10.002
Article CAS PubMed Google Scholar
Zhao T, Zhang ZN, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474(7350):212–215. https://doi.org/10.1038/nature10135
Article CAS PubMed Google Scholar
Zhou W, Freed CR (2009) Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 27(11):2667–2674. https://doi.org/10.1002/stem.201
Article CAS PubMed Google Scholar
Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, Ding S (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4(5):381–384. https://doi.org/10.1016/j.stem.2009.04.005
Article CAS PubMed Google Scholar
Zhou R, Xu A, Gingold J, Strong LC, Zhao R, Lee DF (2017) Li-Fraumeni syndrome disease model: a platform to develop precision Cancer therapy targeting oncogenic p53. Trends Pharmacol Sci 38(10):908–927. https://doi.org/10.1016/j.tips.2017.07.004
Article CAS PubMed PubMed Central Google Scholar
Zhou R, Xu A, Wang D, Zhu D, Mata H, Huo Z, Tu J, Liu M, Mohamed AMT, Jewell BE, Gingold J, Xia W, Rao PH, Hung MC, Zhao R, Lee DF (2018) A homozygous p53 R282W mutant human embryonic stem cell line generated using TALEN-mediated precise gene editing. Stem Cell Res 27:131–135. https://doi.org/10.1016/j.scr.2018.01.035
Article CAS PubMed Google Scholar
Zwaan CM, Kolb EA, Reinhardt D, Abrahamsson J, Adachi S, Aplenc R, De Bont ES, De Moerloose B, Dworzak M, Gibson BE, Hasle H, Leverger G, Locatelli F, Ragu C, Ribeiro RC, Rizzari C, Rubnitz JE, Smith OP, Sung L, Tomizawa D, van den Heuvel-Eibrink MM, Creutzig U, Kaspers GJ (2015) Collaborative efforts driving progress in pediatric acute myeloid leukemia. J Clin Oncol 33(27):2949–2962. https://doi.org/10.1200/JCO.2015.62.8289
Article CAS PubMed PubMed Central Google Scholar

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Acknowledgements

D.-F.L. is the CPRIT scholar in Cancer Research and supported by NIH Pathway to Independence Award R00 CA181496 and CPRIT Award RR160019.

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Authors and Affiliations

Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
Dandan Zhu, Celine Shuet Lin Kong, Ruiying Zhao & Dung-Fang Lee
Women’s Health Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Julian A. Gingold
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
Dung-Fang Lee
Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, USA
Dung-Fang Lee
Center for Precision Health, School of Biomedical Informatics and School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
Dung-Fang Lee

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Dandan Zhu
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Celine Shuet Lin Kong
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Julian A. Gingold
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Ruiying Zhao
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Dung-Fang Lee
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Ottawa Hospital Research Institute, Ottawa, ON, Canada
Kursad Turksen

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Zhu, D., Kong, C.S.L., Gingold, J.A., Zhao, R., Lee, DF. (2018). Induced Pluripotent Stem Cells and Induced Pluripotent Cancer Cells in Cancer Disease Modeling. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 4. Advances in Experimental Medicine and Biology(), vol 1119. Springer, Cham. https://doi.org/10.1007/5584_2018_257

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DOI: https://doi.org/10.1007/5584_2018_257
Published: 02 August 2018
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-10485-6
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