Abstract
Together with recent advances in the processing and culture of human tissue, bioengineering, xenotransplantation and genome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for the study of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and how the method intersects with other patient-derived models of cancer, such as organoids, organs-on-chips and patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can provide beyond those offered by existing systems and animal models and present current challenges and crucial areas for future improvements toward wider adoption of this technology.
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References
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Papapetrou, E.P. Induced pluripotent stem cells, past and future. Science 353, 991–992 (2016).
Onder, T.T. & Daley, G.Q. New lessons learned from disease modeling with induced pluripotent stem cells. Curr. Opin. Genet. Dev. 22, 500–508 (2012).
Zeltner, N. & Studer, L. Pluripotent stem cell-based disease modeling: current hurdles and future promise. Curr. Opin. Cell Biol. 37, 102–110 (2015).
Liu, X. et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am. J. Pathol. 180, 599–607 (2012).
Crystal, A.S. et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346, 1480–1486 (2014).
Sachs, N. & Clevers, H. Organoid cultures for the analysis of cancer phenotypes. Curr. Opin. Genet. Dev. 24, 68–73 (2014).
Fatehullah, A., Tan, S.H. & Barker, N. Organoids as an in vitro model of human development and disease. Nat. Cell Biol. 18, 246–254 (2016).
Ridky, T.W., Chow, J.M., Wong, D.J. & Khavari, P.A. Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia. Nat. Med. 16, 1450–1455 (2010).
Vaira, V. et al. Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors. Proc. Natl. Acad. Sci. USA 107, 8352–8356 (2010).
Majumder, B. et al. Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. Nat. Commun. 6, 6169 (2015).
Gould, S.E., Junttila, M.R. & de Sauvage, F.J. Translational value of mouse models in oncology drug development. Nat. Med. 21, 431–439 (2015).
Day, C.P., Merlino, G. & Van Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39–53 (2015).
Ingber, D.E. Reverse engineering human pathophysiology with organs-on-chips. Cell 164, 1105–1109 (2016).
Hochedlinger, K. et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev. 18, 1875–1885 (2004).
Blelloch, R.H. et al. Nuclear cloning of embryonal carcinoma cells. Proc. Natl. Acad. Sci. USA 101, 13985–13990 (2004).
Carette, J.E. et al. Generation of iPSCs from cultured human malignant cells. Blood 115, 4039–4042 (2010).
Utikal, J., Maherali, N., Kulalert, W. & Hochedlinger, K. Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J. Cell Sci. 122, 3502–3510 (2009).
Miyoshi, N. et al. Defined factors induce reprogramming of gastrointestinal cancer cells. Proc. Natl. Acad. Sci. USA 107, 40–45 (2010).
Zhang, X., Cruz, F.D., Terry, M., Remotti, F. & Matushansky, I. Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene 32, 2249–2260 (2013).
Stricker, S.H. et al. Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev. 27, 654–669 (2013).
Corominas-Faja, B. et al. Nuclear reprogramming of luminal-like breast cancer cells generates Sox2-overexpressing cancer stem-like cellular states harboring transcriptional activation of the mTOR pathway. Cell Cycle 12, 3109–3124 (2013).
Kim, J. & Zaret, K.S. Reprogramming of human cancer cells to pluripotency for models of cancer progression. EMBO J. 34, 739–747 (2015).
Hu, K. et al. Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117, e109–e119 (2011).
Gandre-Babbe, S. et al. Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia. Blood 121, 4925–4929 (2013).
Kumano, K. et al. Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples. Blood 119, 6234–6242 (2012).
Hosoi, M. et al. Generation of induced pluripotent stem cells derived from primary and secondary myelofibrosis patient samples. Exp. Hematol. 42, 816–825 (2014).
Kotini, A.G. et al. Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat. Biotechnol. 33, 646–655 (2015).
Ye, Z. et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 114, 5473–5480 (2009).
Ye, Z. et al. Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient-specific induced pluripotent stem cells. Stem Cells 32, 269–278 (2014).
Mulero-Navarro, S. et al. Myeloid dysregulation in a human induced pluripotent stem cell model of PTPN11-associated juvenile myelomonocytic leukemia. Cell Rep. 13, 504–515 (2015).
Kim, J. et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep. 3, 2088–2099 (2013).
Lee, D.F. et al. Modeling familial cancer with induced pluripotent stem cells. Cell 161, 240–254 (2015).
Müller, L.U. et al. Overcoming reprogramming resistance of Fanconi anemia cells. Blood 119, 5449–5457 (2012).
Antony-Debré, I. et al. Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood 125, 930–940 (2015).
Soyombo, A.A. et al. Analysis of induced pluripotent stem cells from a BRCA1 mutant family. Stem Cell Reports 1, 336–349 (2013).
Takahashi, K. & Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 17, 183–193 (2016).
Apostolou, E. & Hochedlinger, K. Chromatin dynamics during cellular reprogramming. Nature 502, 462–471 (2013).
Jaenisch, R. & Young, R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132, 567–582 (2008).
Papapetrou, E.P. et al. Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation. Proc. Natl. Acad. Sci. USA 106, 12759–12764 (2009).
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Chin, M.H., Pellegrini, M., Plath, K. & Lowry, W.E. Molecular analyses of human induced pluripotent stem cells and embryonic stem cells. Cell Stem Cell 7, 263–269 (2010).
Tapia, N. & Schöler, H.R. Molecular obstacles to clinical translation of iPSCs. Cell Stem Cell 19, 298–309 (2016).
Krijger, P.H. et al. Cell-of-origin-specific 3D genome structure acquired during somatic cell reprogramming. Cell Stem Cell 18, 597–610 (2016).
De Los Angeles, A. et al. Hallmarks of pluripotency. Nature 525, 469–478 (2015).
Chen, K.G., Mallon, B.S., McKay, R.D. & Robey, P.G. Human pluripotent stem cell culture: considerations for maintenance, expansion, and therapeutics. Cell Stem Cell 14, 13–26 (2014).
Rouhani, F. et al. Genetic background drives transcriptional variation in human induced pluripotent stem cells. PLoS Genet. 10, e1004432 (2014).
Kyttälä, A. et al. Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential. Stem Cell Reports 6, 200–212 (2016).
Féraud, O. et al. Donor dependent variations in hematopoietic differentiation among embryonic and induced pluripotent stem cell lines. PLoS One 11, e0149291 (2016).
Burrows, C.K. et al. Genetic variation, not cell type of origin, underlies the majority of identifiable regulatory differences in iPSCs. PLoS Genet. 12, e1005793 (2016).
Utikal, J. et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145–1148 (2009).
Marión, R.M. et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460, 1149–1153 (2009).
Kawamura, T. et al. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460, 1140–1144 (2009).
Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009).
Raya, A. et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460, 53–59 (2009).
Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009).
Ruiz, S. et al. A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr. Biol. 21, 45–52 (2011).
Guo, S. et al. Nonstochastic reprogramming from a privileged somatic cell state. Cell 156, 649–662 (2014).
Papapetrou, E.P. & Sadelain, M. Generation of transgene-free human induced pluripotent stem cells with an excisable single polycistronic vector. Nat. Protoc. 6, 1251–1273 (2011).
Visvader, J.E. Cells of origin in cancer. Nature 469, 314–322 (2011).
Chen, Y. et al. Engineering human stem cell lines with inducible gene knockout using CRISPR/Cas9. Cell Stem Cell 17, 233–244 (2015).
Hrvatin, S. et al. Differentiated human stem cells resemble fetal, not adult, β cells. Proc. Natl. Acad. Sci. USA 111, 3038–3043 (2014).
van den Berg, C.W. et al. Transcriptome of human foetal heart compared with cardiomyocytes from pluripotent stem cells. Development 142, 3231–3238 (2015).
Rowe, R.G., Mandelbaum, J., Zon, L.I. & Daley, G.Q. Engineering hematopoietic stem cells: lessons from development. Cell Stem Cell 18, 707–720 (2016).
Hussein, S.M. et al. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58–62 (2011).
Ji, J. et al. Elevated coding mutation rate during the reprogramming of human somatic cells into induced pluripotent stem cells. Stem Cells 30, 435–440 (2012).
Young, M.A. et al. Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10, 570–582 (2012).
Abyzov, A. et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492, 438–442 (2012).
Cheng, L. et al. Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell 10, 337–344 (2012).
Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010).
Laurent, L.C. et al. 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, 106–118 (2011).
Varela, C. et al. Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells. J. Clin. Invest. 122, 569–574 (2012).
Peterson, S.E. & Loring, J.F. Genomic instability in pluripotent stem cells: implications for clinical applications. J. Biol. Chem. 289, 4578–4584 (2014).
Liang, G. & Zhang, Y. Genetic and epigenetic variations in iPSCs: potential causes and implications for application. Cell Stem Cell 13, 149–159 (2013).
Polo, J.M. et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151, 1617–1632 (2012).
Papp, B. & Plath, K. Epigenetics of reprogramming to induced pluripotency. Cell 152, 1324–1343 (2013).
Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).
Polo, J.M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat. Biotechnol. 28, 848–855 (2010).
Ghosh, Z. et al. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS One 5, e8975 (2010).
Bock, C. et al. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144, 439–452 (2011).
Guenther, M.G. et al. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7, 249–257 (2010).
Choi, J. et al. A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. Nat. Biotechnol. 33, 1173–1181 (2015).
Hockemeyer, D. & Jaenisch, R. Induced pluripotent stem cells meet genome editing. Cell Stem Cell 18, 573–586 (2016).
Sterneckert, J.L., Reinhardt, P. & Schöler, H.R. Investigating human disease using stem cell models. Nat. Rev. Genet. 15, 625–639 (2014).
Cox, D.B., Platt, R.J. & Zhang, F. Therapeutic genome editing: prospects and challenges. Nat. Med. 21, 121–131 (2015).
Maddalo, D. et al. In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 516, 423–427 (2014).
Mandegar, M.A. et al. CRISPR interference efficiently induces specific and reversible gene silencing in human iPSCs. Cell Stem Cell 18, 541–553 (2016).
Kreso, A. & Dick, J.E. Evolution of the cancer stem cell model. Cell Stem Cell 14, 275–291 (2014).
Soldner, F. et al. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533, 95–99 (2016).
Engle, S.J. & Puppala, D. Integrating human pluripotent stem cells into drug development. Cell Stem Cell 12, 669–677 (2013).
Engle, S.J. & Vincent, F. Small molecule screening in human induced pluripotent stem cell-derived terminal cell types. J. Biol. Chem. 289, 4562–4570 (2014).
Lee, G. et al. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat. Biotechnol. 30, 1244–1248 (2012).
Wainger, B.J. et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 7, 1–11 (2014).
Naryshkin, N.A. et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345, 688–693 (2014).
Ogawa, M. et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat. Biotechnol. 33, 853–861 (2015).
Sampaziotis, F. et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat. Biotechnol. 33, 845–852 (2015).
Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).
Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).
Morizane, R. et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat. Biotechnol. 33, 1193–1200 (2015).
Grskovic, M., Javaherian, A., Strulovici, B. & Daley, G.Q. Induced pluripotent stem cells--opportunities for disease modelling and drug discovery. Nat. Rev. Drug Discov. 10, 915–929 (2011).
McCracken, K.W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400–404 (2014).
Watson, C.L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310–1314 (2014).
Dye, B.R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4, e05098 (2015).
Schwartz, M.P. et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc. Natl. Acad. Sci. USA 112, 12516–12521 (2015).
Burridge, P.W. et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 22, 547–556 (2016).
Eggert, U.S. The why and how of phenotypic small-molecule screens. Nat. Chem. Biol. 9, 206–209 (2013).
Friedman, A.A., Letai, A., Fisher, D.E. & Flaherty, K.T. Precision medicine for cancer with next-generation functional diagnostics. Nat. Rev. Cancer 15, 747–756 (2015).
Mertens, J. et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95–99 (2015).
Garbes, L. et al. VPA response in SMA is suppressed by the fatty acid translocase CD36. Hum. Mol. Genet. 22, 398–407 (2013).
Cao, L. et al. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci. Transl. Med. 8, 335ra56 (2016).
Terrenoire, C. et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J. Gen. Physiol. 141, 61–72 (2013).
Maqsood, M.I., Matin, M.M., Bahrami, A.R. & Ghasroldasht, M.M. Immortality of cell lines: challenges and advantages of establishment. Cell Biol. Int. 37, 1038–1045 (2013).
Elenbaas, B. et al. Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 15, 50–65 (2001).
Henderson, E., Miller, G., Robinson, J. & Heston, L. Efficiency of transformation of lymphocytes by Epstein-Barr virus. Virology 76, 152–163 (1977).
Maherali, N. & Hochedlinger, K. Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3, 595–605 (2008).
Suprynowicz, F.A. et al. Conditionally reprogrammed cells represent a stem-like state of adult epithelial cells. Proc. Natl. Acad. Sci. USA 109, 20035–20040 (2012).
Lancaster, M.A. & Knoblich, J.A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).
Clevers, H. Modeling development and disease with organoids. Cell 165, 1586–1597 (2016).
Wu, J. & Izpisua Belmonte, J.C. Stem cells: a renaissance in human biology research. Cell 165, 1572–1585 (2016).
Boj, S.F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).
Huang, L. et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 1364–1371 (2015).
Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141, 1762–1772 (2011).
Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).
van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).
Passier, R., Orlova, V. & Mummery, C. Complex tissue and disease modeling using hiPSCs. Cell Stem Cell 18, 309–321 (2016).
Guye, P. et al. Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6. Nat. Commun. 7, 10243 (2016).
Giobbe, G.G. et al. Functional differentiation of human pluripotent stem cells on a chip. Nat. Methods 12, 637–640 (2015).
Acknowledgements
E.P.P. is supported by US National Institutes of Health (NIH) grants R00 DK087923 and R01 HL121570; by the Lawrence Ellison Foundation; by the Damon Runyon Cancer Research Foundation; by the Edward Evans Foundation; and by the Taub Foundation for MDS research.
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Papapetrou, E. Patient-derived induced pluripotent stem cells in cancer research and precision oncology. Nat Med 22, 1392–1401 (2016). https://doi.org/10.1038/nm.4238
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DOI: https://doi.org/10.1038/nm.4238
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