1932

Abstract

Organoid cultures have emerged as powerful model systems accelerating discoveries in cellular and cancer biology. These three-dimensional cultures are amenable to diverse techniques, including high-throughput genome and transcriptome sequencing, as well as genetic and biochemical perturbation, making these models well suited to answer a variety of questions. Recently, organoids have been generated from diverse human cancers, including breast, colon, pancreas, prostate, bladder, and liver cancers, and studies involving these models are expanding our knowledge of the etiology and characteristics of these malignancies. Co-cultures of cancer organoids with non-neoplastic stromal cells enable investigation of the tumor microenvironment. In addition, recent studies have established that organoids have a place in personalized medicine approaches. Here, we describe the application of organoid technology to cancer discovery and treatment.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030518-055702
2019-03-04
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/3/1/annurev-cancerbio-030518-055702.html?itemId=/content/journals/10.1146/annurev-cancerbio-030518-055702&mimeType=html&fmt=ahah

Literature Cited

  1. Baker LA, Tiriac H, Clevers H, Tuveson DA 2016. Modeling pancreatic cancer with organoids. Trends Cancer 2:176–90
    [Google Scholar]
  2. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ et al. 2010. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6:25–36
    [Google Scholar]
  3. Bartfeld S, Bayram T, van de Wetering M, Huch M, Begthel H et al. 2015. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148:126–36.e6
    [Google Scholar]
  4. Boj SF, Hwang CI, Baker LA, Chio II, Engle DD et al. 2015. Organoid models of human and mouse ductal pancreatic cancer. Cell 160:324–38
    [Google Scholar]
  5. Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarro LM et al. 2017. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 23:1424–35
    [Google Scholar]
  6. Calderon-Gierszal EL, Prins GS 2015. Directed differentiation of human embryonic stem cells into prostate organoids in vitro and its perturbation by low-dose bisphenol A exposure. PLOS ONE 10:e0133238
    [Google Scholar]
  7. Chio IIC, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K et al. 2016. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166:963–76
    [Google Scholar]
  8. Chua CW, Shibata M, Lei M, Toivanen R, Barlow LJ et al. 2014. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat. Cell Biol. 16:951–61
    [Google Scholar]
  9. Cruz-Acuna R, Quiros M, Farkas AE, Dedhia PH, Huang S et al. 2017. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat. Cell Biol. 19:1326–35
    [Google Scholar]
  10. DiMarco RL, Dewi RE, Bernal G, Kuo C, Heilshorn SC 2015. Protein-engineered scaffolds for in vitro 3D culture of primary adult intestinal organoids. Biomater. Sci. 3:1376–85
    [Google Scholar]
  11. Drost J, van Boxtel R, Blokzijl F, Mizutani T, Sasaki N et al. 2017. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science 358:234–38
    [Google Scholar]
  12. Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R et al. 2015. Sequential cancer mutations in cultured human intestinal stem cells. Nature 521:43–47
    [Google Scholar]
  13. Fujii M, Shimokawa M, Date S, Takano A, Matano M et al. 2016. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18:827–827
    [Google Scholar]
  14. Fumagalli A, Drost J, Suijkerbuijk SJ, van Boxtel R, de Ligt J et al. 2017. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. PNAS 114:E2357–64
    [Google Scholar]
  15. Fumagalli A, Suijkerbuijk SJE, Begthel H, Beerling E, Oost KC et al. 2018. A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression. Nat. Protoc. 13:235–47
    [Google Scholar]
  16. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR et al. 2014. Organoid cultures derived from patients with advanced prostate cancer. Cell 159:176–87
    [Google Scholar]
  17. Gjorevski N, Lutolf MP 2017. Synthesis and characterization of well-defined hydrogel matrices and their application to intestinal stem cell and organoid culture. Nat. Protoc. 12:2263–74
    [Google Scholar]
  18. Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina ME et al. 2016. Designer matrices for intestinal stem cell and organoid culture. Nature 539:560–64
    [Google Scholar]
  19. Huang L, Holtzinger A, Jagan I, BeGora M, Lohse I et al. 2015. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21:1364–71
    [Google Scholar]
  20. Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ et al. 2013.a Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J 32:2708–21
    [Google Scholar]
  21. Huch M, Dorrell C, Boj SF, van Es JH, Li VS et al. 2013.b In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494:247–50
    [Google Scholar]
  22. Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F et al. 2015. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160:299–312
    [Google Scholar]
  23. Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R et al. 2014. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159:163–75
    [Google Scholar]
  24. Katano T, Ootani A, Mizoshita T, Tanida S, Tsukamoto H et al. 2013. Establishment of a long-term three-dimensional primary culture of mouse glandular stomach epithelial cells within the stem cell niche. Biochem. Biophys. Res. Commun. 432:558–63
    [Google Scholar]
  25. Kim J, Bamlet WR, Oberg AL, Chaffee KG, Donahue G et al. 2017. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19–9 blood markers. Sci. Transl. Med. 9:eaah5583
    [Google Scholar]
  26. Kim J, Hoffman JP, Alpaugh RK, Rhim AD, Reichert M et al. 2013. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep 3:2088–99
    [Google Scholar]
  27. Kleinman HK, Martin GR 2005. Matrigel: basement membrane matrix with biological activity. Semin. Cancer Biol. 15:378–86
    [Google Scholar]
  28. Lannagan TRM, Lee YK, Wang T, Roper J, Bettington ML et al. 2018. Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis. Gut In press
  29. Lee JH, Bhang DH, Beede A, Huang TL, Stripp BR et al. 2014. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156:440–55
    [Google Scholar]
  30. Lee SH, Hu W, Matulay JT, Silva MV, Owczarek TB et al. 2018. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173:515–28.e17
    [Google Scholar]
  31. Li X, Nadauld L, Ootani A, Corney DC, Pai RK et al. 2014. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat. Med. 20:769–77
    [Google Scholar]
  32. Liu X, Ory V, Chapman S, Yuan H, Albanese C et al. 2012. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am. J. Pathol. 180:599–607
    [Google Scholar]
  33. Matano M, Date S, Shimokawa M, Takano A, Fujii M et al. 2015. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat. Med. 21:256–62
    [Google Scholar]
  34. Merker SR, Weitz J, Stange DE 2016. Gastrointestinal organoids: How they gut it out. Dev. Biol. 420:239–50
    [Google Scholar]
  35. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG et al. 2015. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47:1168–78
    [Google Scholar]
  36. Nguyen-Ngoc KV, Cheung KJ, Brenot A, Shamir ER, Gray RS et al. 2012. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. PNAS 109:E2595–604
    [Google Scholar]
  37. O'Rourke KP, Loizou E, Livshits G, Schatoff EM, Baslan T et al. 2017. Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat. Biotechnol. 35:577–82
    [Google Scholar]
  38. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS et al. 2017. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214:579–96
    [Google Scholar]
  39. Okawa T, Michaylira CZ, Kalabis J, Stairs DB, Nakagawa H et al. 2007. The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation. Genes Dev 21:2788–803
    [Google Scholar]
  40. Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H et al. 2009. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15:701–6
    [Google Scholar]
  41. Pauli C, Hopkins BD, Prandi D, Shaw R, Fedrizzi T et al. 2017. Personalized in vitro and in vivo cancer models to guide precision medicine. Cancer Discov 7:462–77
    [Google Scholar]
  42. Peerani R, Zandstra PW 2010. Enabling stem cell therapies through synthetic stem cell-niche engineering. J. Clin. Investig. 120:60–70
    [Google Scholar]
  43. Petersen OW, Ronnov-Jessen L, Howlett AR, Bissell MJ 1992. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. PNAS 89:9064–68
    [Google Scholar]
  44. Roe JS, Hwang CI, Somerville TDD, Milazzo JP, Lee EJ et al. 2017. Enhancer reprogramming promotes pancreatic cancer metastasis. Cell 170:875–88.e20
    [Google Scholar]
  45. Roerink SF, Sasaki N, Lee-Six H, Young MD, Alexandrov LB et al. 2018. Intra-tumour diversification in colorectal cancer at the single-cell level. Nature 556:457–62
    [Google Scholar]
  46. Roper J, Tammela T, Akkad A, Almeqdadi M, Santos SB et al. 2018. Colonoscopy-based colorectal cancer modeling in mice with CRISPR-Cas9 genome editing and organoid transplantation. Nat. Protoc. 13:217–34
    [Google Scholar]
  47. Roper J, Tammela T, Cetinbas NM, Akkad A, Roghanian A et al. 2017. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis. Nat. Biotechnol. 35:569–76
    [Google Scholar]
  48. Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G et al. 2018. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172:373–86.e10
    [Google Scholar]
  49. Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH et al. 2011. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141:1762–72
    [Google Scholar]
  50. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N et al. 2009. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459:262–65
    [Google Scholar]
  51. Schreiber FS, Deramaudt TB, Brunner TB, Boretti MI, Gooch KJ et al. 2004. Successful growth and characterization of mouse pancreatic ductal cells: functional properties of the Ki-RASG12V oncogene. Gastroenterology 127:250–60
    [Google Scholar]
  52. Seino T, Kawasaki S, Shimokawa M, Tamagawa H, Toshimitsu K et al. 2018. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22:454–67.e6
    [Google Scholar]
  53. Sherr CJ, Beach D, Shapiro GI 2016. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6:353–67
    [Google Scholar]
  54. Steinhart Z, Pavlovic Z, Chandrashekhar M, Hart T, Wang X et al. 2017. Genome-wide CRISPR screens reveal a Wnt–FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. Nat. Med. 23:60–68
    [Google Scholar]
  55. Tan S, Barker N 2013. Engineering the niche for stem cells. Growth Factors 31:175–84
    [Google Scholar]
  56. Tiriac H, Belleau P, Engle DD, Plenker D, Deschênes A et al. 2018. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov 8:1112–29
    [Google Scholar]
  57. Tsai S, McOlash L, Palen K, Johnson B, Duris C et al. 2018. Development of primary human pancreatic cancer organoids, matched stromal and immune cells and 3D tumor microenvironment models. BMC Cancer 18:335
    [Google Scholar]
  58. Usui T, Sakurai M, Enjoji S, Kawasaki H, Umata K et al. 2016. Establishment of a novel model for anticancer drug resistance in three-dimensional primary culture of tumor microenvironment. Stem Cells Int 2016:7053872
    [Google Scholar]
  59. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F et al. 2015. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–45
    [Google Scholar]
  60. Verissimo CS, Overmeer RM, Ponsioen B, Drost J, Mertens S et al. 2016. Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening. eLife 5:e18489
    [Google Scholar]
  61. Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernandez-Mateos J et al. 2018. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359:920–26
    [Google Scholar]
  62. Wang K, Yuen ST, Xu J, Lee SP, Yan HH et al. 2014. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46:573–82
    [Google Scholar]
  63. Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T et al. 2012. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18:618–23
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030518-055702
Loading
  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error