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.

Applications of organoids for cancer biology and precision medicine

Abstract

Organoid technologies enable the creation of in vitro physiologic systems that model tissues of origin more accurately than classical culture approaches. Seminal characteristics of these systems, including three-dimensional structure and recapitulation of self-renewal, differentiation and disease pathology, render organoids eminently suited as hybrids that combine the experimental tractability of traditional two-dimensional cell lines with cellular attributes of in vivo model systems. Here we describe recent advances in this rapidly evolving field and their application to cancer biology, clinical translation and precision medicine.

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 methodologies.
Fig. 2: Bottom-up cancer modeling in wild-type organoids.
Fig. 3: Top-down cancer modeling in patient-derived tumor organoids.

References

  1. Begley, C. G. & Ellis, L. M. Drug development: raise standards for preclinical cancer research. Nature 483, 531–533 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Lancaster, M. A. & Knoblich, J. A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345, 1247125 (2014).

    Article  PubMed  CAS  Google Scholar 

  3. Lancaster, M. A. & Huch, M. Disease modelling in human organoids. Dis. Model. Mech. 12, dmm039347 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Ootani, A. et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15, 701–706 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Fujii, M. et al. Human intestinal organoids maintain self-renewal capacity and cellular diversity in niche-inspired culture condition. Cell Stem Cell 23, 787–793.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Jung, P. et al. Isolation and in vitro expansion of human colonic stem cells. Nat. Med. 17, 1225–1227 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Bartfeld, S. et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148, 126–136.e6 (2015).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Nanduri, L. S. Y. et al. Purification and ex vivo expansion of fully functional salivary gland stem cells. Stem Cell Reports 3, 957–964 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Georgakopoulos, N. et al. Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids. BMC Dev. Biol. 20, 4 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang, D. et al. Long-term expansion of pancreatic islet organoids from resident Procr+ progenitors. Cell 180, 1198–1211.e19 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Loomans, C. J. M. et al. Expansion of adult human pancreatic tissue yields organoids harboring progenitor cells with endocrine differentiation potential. Stem Cell Reports 10, 712–724 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hu, H. et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell 175, 1591–1606.e19 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peng, W. C. et al. Inflammatory cytokine TNFα promotes the long-term expansion of primary hepatocytes in 3D culture. Cell 175, 1607–1619 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sachs, N. et al. Long-term expanding human airway organoids for disease modeling. EMBO J. 38, e100300 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Danahay, H. et al. Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. Cell Reports 10, 239–252 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Tata, P. R. et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503, 218–223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386.e10 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schutgens, F. et al. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat. Biotechnol. 37, 303–313 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Kopper, O. et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat. Med. 25, 838–849 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Hill, S. J. et al. Prediction of DNA repair inhibitor response in short-term patient-derived ovarian cancer organoids. Cancer Discov. 8, 1404–1421 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boonekamp, K. E. et al. Long-term expansion and differentiation of adult murine epidermal stem cells in 3D organoid cultures. Proc. Natl. Acad. Sci. USA 116, 14630–14638 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bhaduri, A. et al. Cell stress in cortical organoids impairs molecular subtype specification. Nature 578, 142–148 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ganesh, K. et al. L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer. Nat. Cancer 1, 28–45 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Co, J. Y. et al. Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Reports 26, 2509–2520 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988.e16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. DiMarco, R. L. et al. Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. Integr. Biol. 6, 127–142 (2014).

    Article  CAS  Google Scholar 

  43. Velasco, S. et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570, 523–527 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Paşca, A. M. et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat. Methods 12, 671–678 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Múnera, J. O. et al. Differentiation of human pluripotent stem cells into colonic organoids via transient activation of BMP signaling. Cell Stem Cell 21, 51–64.e6 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. McCracken, K. W. et al. Wnt/β-catenin promotes gastric fundus specification in mice and humans. Nature 541, 182–187 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Trisno, S. L. et al. Esophageal organoids from human pluripotent stem cells delineate Sox2 functions during esophageal specification. Cell Stem Cell 23, 501–515.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Wong, A. P. et al. Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat. Biotechnol. 30, 876–882 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang, S. X. L. et al. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat. Biotechnol. 32, 84–91 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4, (2015).

  55. Chen, Y. W. et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat. Cell Biol. 19, 542–549 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kurmann, A. A. et al. Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells. Cell Stem Cell 17, 527–542 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Longmire, T. A. et al. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10, 398–411 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Morizane, R. et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat. Biotechnol. 33, 1193–1200 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  60. Ozone, C. et al. Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. Nat. Commun. 7, 10351 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Suga, H. et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature 480, 57–62 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Koehler, K. R., Mikosz, A. M., Molosh, A. I., Patel, D. & Hashino, E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500, 217–221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Koehler, K. R. et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 35, 583–589 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu, X. P., Koehler, K. R., Mikosz, A. M., Hashino, E. & Holt, J. R. Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nat. Commun. 7, 11508 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nakano, T. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10, 771–785 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Lee, J. et al. Hair follicle development in mouse pluripotent stem cell-derived skin organoids. Cell Reports 22, 242–254 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Wimmer, R. A. et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565, 505–510 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 1310–1314 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Phipson, B. et al. Evaluation of variability in human kidney organoids. Nat. Methods 16, 79–87 (2019).

    Article  CAS  PubMed  Google Scholar 

  70. Wu, H. et al. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell 23, 869–881.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. van den Berg, C. W. et al. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem Cell Reports 10, 751–765 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Dye, B. R. et al. A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids. eLife 5, e19732 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. McCauley, H. A. & Wells, J. M. Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development 144, 958–962 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  77. Drost, J. et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521, 43–47 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. IJspeert, J. E. G., Vermeulen, L., Meijer, G. A. & Dekker, E. Serrated neoplasia-role in colorectal carcinogenesis and clinical implications. Nat. Rev. Gastroenterol. Hepatol. 12, 401–409 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lannagan, T. R. M. et al. Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis. Gut 68, 684–692 (2019).

    Article  CAS  PubMed  Google Scholar 

  81. Kawasaki, K. et al. Chromosome engineering of human colon-derived organoids to develop a model of traditional serrated adenoma. Gastroenterology 158, 638–651 (2020).

    Article  CAS  PubMed  Google Scholar 

  82. Davis, H. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 21, 62–70 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  85. van Es, J. H. & Clevers, H. Generation and analysis of mouse intestinal tumors and organoids harboring APC and K-Ras mutations. Methods Mol. Biol. 1267, 125–144 (2015).

    Article  PubMed  CAS  Google Scholar 

  86. Nanki, K. et al. Divergent routes toward Wnt and R-spondin niche independency during human gastric carcinogenesis. Cell 174, 856–869.e17 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Lee, J. et al. Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells. Nat. Commun. 8, 14686 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. Liu, X. et al. Modeling Wnt signaling by CRISPR-Cas9 genome editing recapitulates neoplasia in human Barrett epithelial organoids. Cancer Lett. 436, 109–118 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dekkers, J. F. et al. Modeling breast cancer using CRISPR-Cas9-mediated engineering of human breast organoids. J. Natl. Cancer Inst. 112, 540–544 (2020).

    Article  PubMed  CAS  Google Scholar 

  91. Artegiani, B. et al. Probing the tumor suppressor function of BAP1 in CRISPR-engineered human liver organoids. Cell Stem Cell 24, 927–943.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Kim, J. et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Reports 3, 2088–2099 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bian, S. et al. Genetically engineered cerebral organoids model brain tumor formation. Nat. Methods 15, 631–639 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee, D. F. et al. Modeling familial cancer with induced pluripotent stem cells. Cell 161, 240–254 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Han, T. et al. R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nat. Commun. 8, 15945 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang, H. et al. Gain-of-function RHOA mutations promote focal adhesion kinase activation and dependency in diffuse gastric cancer. Cancer Discov. 10, 288–305 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bass, A. J. et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

    Article  CAS  Google Scholar 

  100. Han, K. et al. CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities. Nature 580, 136–141 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Wang, Y. et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512, 155–160 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Roerink, S. F. et al. Intra-tumour diversification in colorectal cancer at the single-cell level. Nature 556, 457–462 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pollen, A. A. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 176, 743–756.e17 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Christensen, S. et al. 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer. Nat. Commun. 10, 4571 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Bolhaqueiro, A. C. F. et al. Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nat. Genet. 51, 824–834 (2019).

    Article  CAS  PubMed  Google Scholar 

  109. Kretzschmar, K. & Watt, F. M. Lineage tracing. Cell 148, 33–45 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Cortina, C. et al. A genome editing approach to study cancer stem cells in human tumors. EMBO Mol. Med. 9, 869–879 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shimokawa, M. et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545, 187–192 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Sugimoto, S. et al. Reconstruction of the human colon epithelium in vivo. Cell Stem Cell 22, 171–176.e5 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  118. Fumagalli, A. et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 26, 569–578 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. de Sousa E Melo, F. et al. Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 9, 476–485 (2011).

    Article  PubMed  CAS  Google Scholar 

  120. Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Yan, K. S. et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl. Acad. Sci. USA 109, 466–471 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Heo, I. et al. Modelling Cryptosporidium infection in human small intestinal and lung organoids. Nat. Microbiol. 3, 814–823 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Forbester, J. L. et al. Interaction of Salmonella enterica serovar Typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect. Immun. 83, 2926–2934 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  125. Wilson, S. S., Tocchi, A., Holly, M. K., Parks, W. C. & Smith, J. G. A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol. 8, 352–361 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Zhang, Y. G., Wu, S., Xia, Y. & Sun, J. Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol. Rep. 2, e12147 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Pleguezuelos-Manzano, C. et al. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature 580, 269–273 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wroblewski, L. E. et al. Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64, 720–730 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Bertaux-Skeirik, N. et al. CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation. PLoS Pathog. 11, e1004663 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Finkbeiner, S. R. et al. Stem cell-derived human intestinal organoids as an infection model for rotaviruses. MBio 3, e00159–e12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ettayebi, K. et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 353, 1387–1393 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Hui, K. P. Y. et al. Tropism, replication competence, and innate immune responses of influenza virus: an analysis of human airway organoids and ex-vivo bronchus cultures. Lancet Respir. Med. 6, 846–854 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Wirbel, J. et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat. Med. 25, 679–689 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  135. Bleijs, M., van de Wetering, M., Clevers, H. & Drost, J. Xenograft and organoid model systems in cancer research. EMBO J. 38, e101654 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jacob, F. et al. A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell 180, 188–204 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Yan, H. H. N. et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell 23, 882–897.e11 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Vlachogiannis, G. et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920–926 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Schumacher, D. et al. Heterogeneous pathway activation and drug response modelled in colorectal-tumor-derived 3D cultures. PLoS Genet. 15, e1008076 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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).

    Article  CAS  PubMed  Google Scholar 

  145. Ooft, S. N. et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci. Transl. Med. 11, eaay2574 (2019).

    Article  CAS  PubMed  Google Scholar 

  146. Ganesh, K. et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat. Med. 25, 1607–1614 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Yao, Y. et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 26, 17–26 (2020).

    Article  CAS  PubMed  Google Scholar 

  148. Steele, N. G. et al. An organoid-based preclinical model of human gastric cancer. Cell. Mol. Gastroenterol. Hepatol. 7, 161–184 (2019).

    Article  PubMed  Google Scholar 

  149. Seidlitz, T. et al. Human gastric cancer modelling using organoids. Gut 68, 207–217 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Tiriac, H. et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. 8, 1112–1129 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Driehuis, E. et al. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proc. Natl. Acad. Sci. USA 116, 26580–26590 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  152. Mullenders, J. et al. Mouse and human urothelial cancer organoids: A tool for bladder cancer research. Proc. Natl. Acad. Sci. USA 116, 4567–4574 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lee, S. H. et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173, 515–528 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Puca, L. et al. Patient derived organoids to model rare prostate cancer phenotypes. Nat. Commun. 9, 2404 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. de Witte, C. J. et al. Patient-derived ovarian cancer organoids mimic clinical response and exhibit heterogeneous inter- and intrapatient drug responses. Cell Reports 31, 107762 (2020).

    Article  PubMed  CAS  Google Scholar 

  156. Kijima, T. et al. Three-dimensional organoids reveal therapy resistance of esophageal and oropharyngeal squamous cell carcinoma cells. Cell. Mol. Gastroenterol. Hepatol. 7, 73–91 (2019).

    Article  PubMed  Google Scholar 

  157. Li, X. et al. Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics. Nat. Commun. 9, 2983 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Driehuis, E. et al. Oral mucosal organoids as a potential platform for personalized cancer therapy. Cancer Discov. 9, 852–871 (2019).

    Article  CAS  PubMed  Google Scholar 

  159. Boretto, M. et al. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat. Cell Biol. 21, 1041–1051 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Li, L. et al. Human primary liver cancer organoids reveal intratumor and interpatient drug response heterogeneity. JCI Insight 4, 121490 (2019).

    Article  PubMed  Google Scholar 

  161. Nuciforo, S. et al. Organoid models of human liver cancers derived from tumor needle biopsies. Cell Reports 24, 1363–1376 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Calandrini, C. et al. An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity. Nat. Commun. 11, 1310 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kim, M. et al. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat. Commun. 10, 3991 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. HCMI. Human Cancer Models Initiative. https://ocg.cancer.gov/programs/HCMI (2020).

  166. De Roock, W. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11, 753–762 (2010).

    Article  PubMed  CAS  Google Scholar 

  167. Sonnenblick, A., de Azambuja, E., Azim, H. A. Jr. & Piccart, M. An update on PARP inhibitors—moving to the adjuvant setting. Nat. Rev. Clin. Oncol. 12, 27–41 (2015).

    Article  CAS  PubMed  Google Scholar 

  168. Vitale, I., Manic, G., Coussens, L. M., Kroemer, G. & Galluzzi, L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 30, 36–50 (2019).

    Article  CAS  PubMed  Google Scholar 

  169. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kalbasi, A. & Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 20, 25–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  172. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).

    Article  PubMed  Google Scholar 

  173. Biffi, G. et al. Il1-induced Jak/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. (2019).

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Schnalzger, T. E. et al. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. EMBO J. 38, e100928 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Dijkstra, K. K. et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174, 1586–1598 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  178. Weeber, F., Ooft, S. N., Dijkstra, K. K. & Voest, E. E. Tumor organoids as a pre-clinical cancer model for drug discovery. Cell Chem. Biol. 24, 1092–1100 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Edmondson, R., Broglie, J. J., Adcock, A. F. & Yang, L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev. Technol. 12, 207–218 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Jabs, J. et al. Screening drug effects in patient-derived cancer cells links organoid responses to genome alterations. Mol. Syst. Biol. 13, 955 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Skardal, A. et al. Drug compound screening in single and integrated multi-organoid body-on-a-chip systems. Biofabrication 12, 025017 (2020).

    Article  CAS  PubMed  Google Scholar 

  185. Geurts, M. H. et al. CRISPR-based adenine editors correct nonsense mutations in a cystic fibrosis organoid biobank. Cell Stem Cell 26, 503–510 (2020).

    Article  CAS  PubMed  Google Scholar 

  186. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  189. Artegiani, B. et al. Fast and efficient generation of knock-in human organoids using homology-independent CRISPR-Cas9 precision genome editing. Nat. Cell Biol. 22, 321–331 (2020).

    Article  CAS  PubMed  Google Scholar 

  190. Vaidyanathan, S. et al. High-efficiency, selection-free gene repair in airway stem cells from cystic fibrosis patients rescues CFTR function in differentiated epithelia. Cell Stem Cell 26, 161–171 (2020).

    Article  CAS  PubMed  Google Scholar 

  191. Michels, B. E. et al. Pooled in vitro and in vivo CRISPR-Cas9 screening identifies tumor suppressors in human colon organoids. Cell Stem Cell 26, 782–792 (2020).

    Article  CAS  PubMed  Google Scholar 

  192. Ringel, T. et al. Genome-scale CRISPR screening in human intestinal organoids identifies drivers of TGF-β resistance. Cell Stem Cell 26, 431–440 (2020).

    Article  CAS  PubMed  Google Scholar 

  193. Du, Y. et al. Development of a miniaturized 3D organoid culture platform for ultra-high throughput screening. J. Mol. Cell Biol. https://doi.org/10.1093/jmcb/mjaa036 (2020).

Download references

Acknowledgements

We thank members of the Kuo lab for discussions and Amanda Mah for figure artwork. This work was supported by US National Institutes of Health fellowship K00CA212433 (Y.-H. L.), a Swedish Research Council International Postdoctoral Fellowship (K. K.), and grants from the NIH (U01CA217851, U54CA224081, U01CA199241 and U19AI116484), Emerson Collective and Ludwig Cancer Research to C. J. K.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Calvin J. Kuo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lo, YH., Karlsson, K. & Kuo, C.J. Applications of organoids for cancer biology and precision medicine. Nat Cancer 1, 761–773 (2020). https://doi.org/10.1038/s43018-020-0102-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43018-020-0102-y

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