Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Organoids in cancer research

Abstract

The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Genetic modification of organoids allows disease modelling in a setting that approaches the physiological environment. Additionally, organoids can be grown with high efficiency from patient-derived healthy and tumour tissues, potentially enabling patient-specific drug testing and the development of individualized treatment regimens. In this Review, we evaluate tumour organoid protocols and how they can be utilized as an alternative model for cancer research.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Organoid cultures for personalized cancer treatment and drug development.
Fig. 2: Organoid cultures to study mutational processes underlying tumorigenesis.

References

  1. Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    PubMed  Article  Google Scholar 

  2. Kamb, A. What’s wrong with our cancer models? Nat. Rev. Drug Discov. 4, 161–165 (2005).

    PubMed  Article  CAS  Google Scholar 

  3. Caponigro, G. & Sellers, W. R. Advances in the preclinical testing of cancer therapeutic hypotheses. Nat. Rev. Drug Discov. 10, 179–187 (2011).

    PubMed  Article  CAS  Google Scholar 

  4. Cheon, D. J. & Orsulic, S. Mouse models of cancer. Annu. Rev. Pathol. 6, 95–119 (2011).

    PubMed  Article  CAS  Google Scholar 

  5. Liu, X. et al. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am. J. Pathol. 180, 599–607 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. Ben-David, U. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat. Genet. 49, 1567–1575 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. Byrne, A. T. et al. Interrogating open issues in cancer medicine with patient-derived xenografts. Nat. Rev. Cancer. 17, 254–268 (2017).

    PubMed  Article  CAS  Google Scholar 

  8. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009). Sato and colleagues describe the generation of organoids from mouse intestinal stem cells, which initiated the development of many other adult stem cell-derived organoid culture protocols.

    PubMed  Article  CAS  Google Scholar 

  9. Carmon, K. S., Gong, X., Lin, Q., Thomas, A. & Liu, Q. R-Spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc. Natl Acad. Sci. USA 108, 11452–11457 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  10. de Lau, W. et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293–297 (2011).

    PubMed  Article  CAS  Google Scholar 

  11. Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011). This paper describes the generation and long-term expansion of patient-derived organoids from normal and cancerous colon tissue.

    PubMed  Article  CAS  Google Scholar 

  12. Jung, P. et al. Isolation and in vitro expansion of human colonic stem cells. Nat. Med. 17, 1225–1227 (2011). This paper describes the establishment of human colon organoids from a single cell.

    PubMed  Article  CAS  Google Scholar 

  13. Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).

    PubMed  Article  CAS  Google Scholar 

  15. Karthaus, W. R. et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159, 163–175 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Chua, C. W. et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat. Cell Biol. 16, 951–961 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Bartfeld, S. et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148, 126–136 e126 (2015).

    PubMed  Article  Google Scholar 

  18. Kessler, M. et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat. Commun. 6, 8989 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. Ren, W. et al. Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo. Proc. Natl Acad. Sci. USA 111, 16401–16406 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. Maimets, M. et al. Long-term in vitro expansion of salivary gland stem cells driven by wnt signals. Stem Cell Rep. 6, 150–162 (2016).

    Article  CAS  Google Scholar 

  21. DeWard, A. D., Cramer, J. & Lagasse, E. Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell population. Cell Rep. 9, 701–711 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Rock, J. R. et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  23. Turco, M. Y. et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat. Cell Biol. 19, 568–577 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386.e10 (2017).

    PubMed  Article  CAS  Google Scholar 

  25. Clevers, H. Modeling development and disease with organoids. Cell 165, 1586–1597 (2016).

    PubMed  Article  CAS  Google Scholar 

  26. Ootani, A. et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15, 701–706 (2009). Ootani and colleagues develop an organoid culture system for intestinal epithelium using an air–liquid interface and underlying stromal elements.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Papapetrou, E. P. Patient-derived induced pluripotent stem cells in cancer research and precision oncology. Nat. Med. 22, 1392–1401 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015). This paper describes the generation of the first organoid biobank consisting of primary tumour and matching healthy organoids from patients with CRC.

    PubMed  Article  CAS  Google Scholar 

  29. Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18, 827–838 (2016).

    PubMed  Article  CAS  Google Scholar 

  30. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Broutier, L. et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 23, 1424–1435 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Weeber, F. et al. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases. Proc. Natl Acad. Sci. USA 112, 13308–13311 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Drost, J. et al. Organoid culture systems for prostate epithelial and cancer tissue. Nat. Protoc. 11, 347–358 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. Drost, J. et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521, 43–47 (2015). Starting from healthy colon organoids, Drost and colleagues use CRISPR technology to introduce common CRC mutations and study tumour progression and chromosome instability.

    PubMed  Article  CAS  Google Scholar 

  36. Verissimo, C. S. et al. Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening. eLife 5, pii: e18489 (2016).

    Article  CAS  Google Scholar 

  37. Cancer Genome Atlas, N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

    Article  CAS  Google Scholar 

  38. Sakamoto, N. et al. BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. eLife 6, pii: e20331 (2017).

    Article  Google Scholar 

  39. Kondo, J. et al. Retaining cell-cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer. Proc. Natl Acad. Sci. USA 108, 6235–6240 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  40. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol. 5, 100–107 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Hao, H. X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200 (2012).

    PubMed  Article  CAS  Google Scholar 

  42. Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

    PubMed  Article  CAS  Google Scholar 

  43. Cristobal, A. et al. Personalized proteome profiles of healthy and tumor human colon organoids reveal both individual diversity and basic features of colorectal cancer. Cell Rep. 18, 263–274 (2017).

    PubMed  Article  CAS  Google Scholar 

  44. Schutte, M. et al. Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors. Nat. Commun. 8, 14262 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Seino, T. et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22, 454–467.e6 (2018).

    PubMed  Article  CAS  Google Scholar 

  46. Barretina, J. et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. Vlachogiannis, G. et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018). In this paper, Vlachogiannis and colleagues describe for the first time that drug responses in patient-derived tumour organoids recapitulate patient responses in the clinic.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  48. Shenoy, T. R. et al. CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair. Ann. Oncol. 28, 1495–1507 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  49. Crespo, M. et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat. Med. 23, 878–884 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  50. Ballet, F. Hepatotoxicity in drug development: detection, significance and solutions. J. Hepatol. 26 (Suppl. 2), 26–36 (1997).

    PubMed  Article  CAS  Google Scholar 

  51. Meng, Q. Three-dimensional culture of hepatocytes for prediction of drug-induced hepatotoxicity. Expert Opin. Drug Metab. Toxicol. 6, 733–746 (2010).

    PubMed  Article  CAS  Google Scholar 

  52. Katsuda, T. et al. Conversion of terminally committed hepatocytes to culturable bipotent progenitor cells with regenerative capacity. Cell Stem Cell 20, 41–55 (2016).

    PubMed  Article  CAS  Google Scholar 

  53. Eder, A., Vollert, I., Hansen, A. & Eschenhagen, T. Human engineered heart tissue as a model system for drug testing. Adv. Drug Deliv. Rev. 96, 214–224 (2016).

    PubMed  Article  CAS  Google Scholar 

  54. Voges, H. K. et al. Development of a human cardiac organoid injury model reveals innate regenerative potential. Development 144, 1118–1127 (2017).

    PubMed  Article  CAS  Google Scholar 

  55. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).

    PubMed  Article  CAS  Google Scholar 

  56. Dekkers, J. F. et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat. Med. 19, 939–945 (2013).

    PubMed  Article  CAS  Google Scholar 

  57. Dekkers, J. F. et al. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med 8, 344ra384 (2016).

    Article  CAS  Google Scholar 

  58. Groenendijk, F. H. & Bernards, R. Drug resistance to targeted therapies: deja vu all over again. Mol. Oncol. 8, 1067–1083 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. Bernards, R. A missing link in genotype-directed cancer therapy. Cell 151, 465–468 (2012).

    PubMed  Article  CAS  Google Scholar 

  60. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    PubMed  Article  CAS  Google Scholar 

  61. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).

    PubMed  Article  CAS  Google Scholar 

  62. Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Rizvi, N. A. et al. Cancer immunology. mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. Sato, T. & Clevers, H. Snapshot: growing organoids from stem cells. Cell 161, 1700–1700 e1 (2015).

    PubMed  Article  CAS  Google Scholar 

  65. Le, D. T. et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Nozaki, K. et al. Co-culture with intestinal epithelial organoids allows efficient expansion and motility analysis of intraepithelial lymphocytes. J. Gastroenterol. 51, 206–213 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Finnberg, N. K. et al. Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures. Oncotarget 8, 66747–66757 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  68. Zumwalde, N. A. et al. Analysis of immune cells from human mammary ductal epithelial organoids reveals Vdelta2+ T Cells that efficiently target breast carcinoma cells in the presence of bisphosphonate. Cancer Prev. Res. 9, 305–316 (2016).

    Article  CAS  Google Scholar 

  69. Stronen, E. et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352, 1337–1341 (2016).

    PubMed  Article  CAS  Google Scholar 

  70. Tajima, A., Pradhan, I., Trucco, M. & Fan, Y. Restoration of thymus function with bioengineered thymus organoids. Curr. Stem Cell Rep. 2, 128–139 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. De Flora, S. & Bonanni, P. The prevention of infection-associated cancers. Carcinogenesis 32, 787–795 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. Salama, N. R., Hartung, M. L. & Muller, A. Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat. Rev. Microbiol. 11, 385–399 (2013).

    PubMed  Article  CAS  Google Scholar 

  73. Huang, J. Y. et al. Chemodetection and destruction of host urea allows Helicobacter pylori to locate the epithelium. Cell Host Microbe 18, 147–156 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400–404 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. Scanu, T. et al. Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell Host Microbe 17, 763–774 (2015).

    PubMed  Article  CAS  Google Scholar 

  76. Yin, Y. et al. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antiviral Res. 123, 120–131 (2015).

    PubMed  Article  CAS  Google Scholar 

  77. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014). This study is the first to exploit genome sequencing of clonal organoids as a tool to study mutational processes.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    PubMed  Article  CAS  Google Scholar 

  83. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    PubMed  Article  CAS  Google Scholar 

  84. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    PubMed  Article  CAS  Google Scholar 

  85. Drost, J. et al. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science 358, 234–238 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  86. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).

    PubMed  Article  CAS  Google Scholar 

  88. Pauli, C. et al. Personalized in vitro and in vivo cancer models to guide precision medicine. Cancer Discov. 7, 462–477 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  89. Roerink, S. et al. A high-resolution molecular history of intra-cancer diversification. Nature https://doi.org/10.1038/s41586-018-0024-3 (2018).

  90. Lugli, N. et al. Enhanced rate of acquisition of point mutations in mouse intestinal adenomas compared to normal tissue. Cell Rep. 19, 2185–2192 (2017).

    PubMed  Article  CAS  Google Scholar 

  91. Matano, M. et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat. Med. 21, 256–262 (2015).

    PubMed  Article  CAS  Google Scholar 

  92. Rajagopalan, H., Nowak, M. A., Vogelstein, B. & Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nat. Rev. Cancer 3, 695–701 (2003).

    PubMed  Article  CAS  Google Scholar 

  93. Fumagalli, A. et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proc. Natl Acad. Sci. USA 114, E2357–E2364 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. Fumagalli, A. et al. A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression. Nat. Protoc. 13, 235–247 (2018).

    PubMed  Article  CAS  Google Scholar 

  95. Li, X. et al. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat. Med. 20, 769–777 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. Melo, F. S. et al. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 543, 676–680 (2017).

    Article  CAS  Google Scholar 

  97. O’Rourke, K. P. et al. Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat. Biotechnol. 35, 577–582 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. Roper, J. et al. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat. Biotechnol. 35, 569–576 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. Shimokawa, M. et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545, 187–192 (2017). References 96 and 99 describe the use of intestinal organoids to study the contribution of CSCs to primary and metastatic CRC.

    PubMed  Article  CAS  Google Scholar 

  100. Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).

    PubMed  Article  CAS  Google Scholar 

  101. Leggett, B. & Whitehall, V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138, 2088–2100 (2010).

    PubMed  Article  CAS  Google Scholar 

  102. Fessler, E. et al. TGFbeta signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Mol. Med. 8, 745–760 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Yan, H. H. et al. RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation. Gut 66, 1645–1656 (2016).

    PubMed  Article  Google Scholar 

  104. Schwank, G. et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13, 653–658 (2013).

    PubMed  Article  CAS  Google Scholar 

  105. Koo, B. K., van Es, J. H., van den Born, M. & Clevers, H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43; Znrf3-mutant neoplasia. Proc. Natl Acad. Sci. USA 112, 7548–7550 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. Nadauld, L. D. et al. Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer. Genome Biol. 15, 428 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  107. Dow, L. E. et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 161, 1539–1552 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. Yin, X. et al. Engineering stem cell organoids. Cell Stem Cell 18, 25–38 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. Workman, M. J. et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat. Med. 23, 49–59 (2017).

    PubMed  Article  CAS  Google Scholar 

  110. Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  111. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016). In this paper, Gjorevski and colleagues engineer synthetic matrices supporting expansion of intestinal organoids, which hold great potential for the applications of organoids in regenerative medicine.

    PubMed  Article  CAS  Google Scholar 

  112. Janda, C. Y. et al. Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling. Nature 545, 234–237 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. Mihara, E. et al. Active and water-soluble form of lipidated Wnt protein is maintained by a serum glycoprotein afamin/alpha-albumin. eLife 5, pii: e11621 (2016).

    Article  Google Scholar 

  114. Tuysuz, N. et al. Lipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells. Nat. Commun. 8, 14578 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  115. Hubert, C. G. et al. A three-dimensional organoid culture system derived from human glioblastomas recapitulates the hypoxic gradients and cancer stem cell heterogeneity of tumors found in vivo. Cancer Res. 76, 2465–2477 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. Sachs, N. & Clevers, H. Organoid cultures for the analysis of cancer phenotypes. Curr. Opin. Genet. Dev. 24, 68–73 (2014).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank K. Kretzschmar and J. Meijerink for critical reading of the manuscript. We are grateful for support from the Dutch Cancer Society (KWF) and the Alpe d’HuZes Bas Mulder Award to J.D. (KWF/Alpe d’HuZes, 10218) and for the support of Oncode Institute to H.C.

Author information

Authors and Affiliations

Authors

Contributions

J.D. and H.C. researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Jarno Drost.

Ethics declarations

Competing interests

J.D. and H.C. are named as inventors on several patents related to leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)+ stem cell-based organoid technology.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Karyotype

The number and appearance of chromosomes in the nucleus of a cell.

Feeder cells

A layer of cells that is used to support the growth of a cell culture (that is, stem cell cultures) by secretion of important growth factors into the culture medium.

Matrigel

A mouse-derived ex vivo basement membrane substitute that is used to support 3D growth of organoid cultures.

Intraepithelial lymphocytes

(IELs). Lymphocytes residing in the epithelial layer of mammalian mucosal linings, such as the small and large intestines, lungs, upper respiratory tract, reproductive tract and skin.

Mutation signatures

Unique combinations of mutation types caused by different mutational processes.

Base excision repair

A DNA repair mechanism that removes damaged bases (oxidized, alkylated or deaminated) that could otherwise cause mutations.

Caecum

A pouch located between the small and large intestine that is considered to be the beginning of the large intestine and is thus part of the gastrointestinal tract.

Anoikis

A process of programmed cell death initiated by loss of cell–matrix interactions in anchorage-dependent cells.

Serrated colon adenomas

A precursor colorectal cancer (CRC) subtype that is characterized by a serrated histopathological morphology. Serrated CRCs are genetically distinct from the classical adenocarcinomas. Whereas classical adenocarcinomas are typically initiated by mutations in the WNT pathway (for example, adenomatous polyposis coli (APC)), serrated CRCs are likely initiated by BRAF mutations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Drost, J., Clevers, H. Organoids in cancer research. Nat Rev Cancer 18, 407–418 (2018). https://doi.org/10.1038/s41568-018-0007-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-018-0007-6

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer