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Next-generation cancer organoids

Nature Materials volume 21, pages 143–159 (2022)Cite this article

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Abstract

Organotypic models of patient-specific tumours are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. These advancements are, in part, attributed to the ability of organoid models to stably preserve genetic, proteomic, morphological and pharmacotypic features of the parent tumour in vitro, while also offering unprecedented genomic and environmental manipulation. Despite recent innovations in organoid protocols, current techniques for cancer organoid culture are inherently uncontrolled and irreproducible, owing to several non-standardized facets including cancer tissue sources and subsequent processing, medium formulations, and animal-derived three-dimensional matrices. Given the potential for cancer organoids to accurately recapitulate the intra- and intertumoral biological heterogeneity associated with patient-specific cancers, eliminating the undesirable technical variability accompanying cancer organoid culture is necessary to establish reproducible platforms that accelerate translatable insights into patient care. Here we describe the current challenges and recent multidisciplinary advancements and opportunities for standardizing next-generation cancer organoid systems.

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Fig. 1: Cancer organoids recapitulate defining characteristics of patient-specific tumour heterogeneity.
Fig. 2: Current techniques for cancer organoid culture introduce technical variability into biologically heterogeneous cultures.
Fig. 3: Patient-specific cancer organoid derivation is limited by non-standardized methods of tissue procurement and processing.
Fig. 4: The ECM influences cancer organoid phenotype through several biochemical and mechanical interactions.
Fig. 5: Engineered matrices for standardizing cancer organoid models.

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References

  1. Bedard, P. L., Hansen, A. R., Ratain, M. J. & Siu, L. L. Tumour heterogeneity in the clinic. Nature 501, 355–364 (2013).

    Article  CAS  Google Scholar 

  2. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).

    Article  CAS  Google Scholar 

  3. Catenacci, D. V. T. Next-generation clinical trials: novel strategies to address the challenge of tumor molecular heterogeneity. Mol. Oncol. 9, 967–996 (2015).

    Article  CAS  Google Scholar 

  4. Turajlic, S., Sottoriva, A., Graham, T. & Swanton, C. Resolving genetic heterogeneity in cancer. Nat. Rev. Genet. 20, 404–416 (2019).

    Article  CAS  Google Scholar 

  5. Meacham, C. E. & Morrison, S. J. Tumour heterogeneity and cancer cell plasticity. Nature 501, 328–337 (2013).

    Article  CAS  Google Scholar 

  6. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the Rosetta Stone of therapy resistance. Cancer Cell 37, 471–484 (2020).

    Article  CAS  Google Scholar 

  7. Runa, F. et al. Tumor microenvironment heterogeneity: challenges and opportunities. Curr. Mol. Biol. Rep. 3, 218–229 (2017).

    Article  CAS  Google Scholar 

  8. Qian, J. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res. 30, 745–762 (2020).

    Article  CAS  Google Scholar 

  9. Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer 18, 407–418 (2018).

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. 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  Google Scholar 

  20. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Kodack, D. P. et al. Primary patient-derived cancer cells and their potential for personalized cancer patient care. Cell Rep. 21, 3298–3309 (2017).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. 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  Google Scholar 

  27. Lee, S. H. et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173, 515–528.e17 (2018).

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

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

    Article  Google Scholar 

  30. Sachs, N. et al. Long‐term expanding human airway organoids for disease modeling. EMBO J. 38, 1–20 (2019).

    Article  Google Scholar 

  31. 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  Google Scholar 

  32. 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  Google Scholar 

  33. Jacob, F. et al. A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell 180, 188–204.e22 (2020).

    Article  CAS  Google Scholar 

  34. Dijkstra, K. K. et al. Challenges in establishing pure lung cancer organoids limit their utility for personalized medicine. Cell Rep. 31, 107588 (2020).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Bock, C. et al. The Organoid Cell Atlas. Nat. Biotechnol. 39, 13–17 (2021).

    Article  CAS  Google Scholar 

  37. Baker, L. A., Tiriac, H., Clevers, H. & Tuveson, D. A. Modeling pancreatic cancer with organoids. Trends Cancer 2, 176–190 (2016).

    Article  Google Scholar 

  38. Driehuis, E., Kretzschmar, K. & Clevers, H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat. Protoc. 15, 3380–3409 (2020).

    Article  CAS  Google Scholar 

  39. Roerink, S. F. et al. Intra-tumour diversification in colorectal cancer at the single-cell level. Nature 556, 437–462 (2018).

    Article  Google Scholar 

  40. Walsh, A. J., Cook, R. S., Sanders, M. E., Arteaga, C. L. & Skala, M. C. Drug response in organoids generated from frozen primary tumor tissues. Sci. Rep. 6, 18889 (2016).

    Article  CAS  Google Scholar 

  41. Brandenberg, N. et al. High-throughput automated organoid culture via stem-cell aggregation in microcavity arrays. Nat. Biomed. Eng. 4, 863–874 (2020).

    Article  CAS  Google Scholar 

  42. Horowitz, L. F. et al. Microdissected ‘cuboids’ for microfluidic drug testing of intact tissues. Lab Chip 21, 122–142 (2021).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. 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 

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

    Article  Google Scholar 

  46. Ebbing, E. A. et al. Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma. Proc. Natl Acad. Sci. USA 116, 2237–2242 (2019).

    Article  CAS  Google Scholar 

  47. Umkehrer, C. et al. Isolating live cell clones from barcoded populations using CRISPRa-inducible reporters. Nat. Biotechnol. 39, 174–178 (2021).

    Article  CAS  Google Scholar 

  48. Kassis, T., Hernandez-Gordillo, V., Langer, R. & Griffith, L. G. OrgaQuant: human intestinal organoid localization and quantification using deep convolutional neural networks. Sci. Rep. 9, 12479 (2019).

    Article  Google Scholar 

  49. Haase, K., Offeddu, G. S., Gillrie, M. R. & Kamm, R. D. Endothelial regulation of drug transport in a 3D vascularized tumor model. Adv. Funct. Mater. 30, 2002444 (2020).

    Article  CAS  Google Scholar 

  50. Chen, M. B. et al. On-chip human microvasculature assay for visualization and quantification of tumor cell extravasation dynamics. Nat. Protoc. 12, 865–880 (2017).

    Article  CAS  Google Scholar 

  51. Nikolaev, M. et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature 585, 574–578 (2020).

    Article  Google Scholar 

  52. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003).

    Article  CAS  Google Scholar 

  53. Tüysüz, N. et al. Lipid-mediated Wnt protein stabilization enables serum-free culture of human organ stem cells. Nat. Commun. 8, 2014–1723 (2017).

    Article  Google Scholar 

  54. Johnson, M. Fetal bovine serum. Mater. Methods 2, 117 (2012).

    Google Scholar 

  55. Anderson, N. L. et al. The human plasma proteome. Mol. Cell. Proteom. 3, 311–326 (2004).

    Article  CAS  Google Scholar 

  56. van der Valk, J. et al. Optimization of chemically defined cell culture media—replacing fetal bovine serum in mammalian in vitro methods. Toxicol. Vitr. 24, 1053–1063 (2010).

    Article  Google Scholar 

  57. 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  Google Scholar 

  58. Urbischek, M. et al. Organoid culture media formulated with growth factors of defined cellular activity. Sci. Rep. 9, 6193 (2019).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  60. Miao, Y. et al. Next-generation surrogate Wnts support organoid growth and deconvolute Frizzled pleiotropy in vivo. Cell Stem Cell 27, 840-851.E6 (2020).

  61. Luca, V. C. et al. Surrogate R-spondins for tissue-specific potentiation of Wnt signaling. PLoS ONE 15, e0226928 (2020).

    Article  CAS  Google Scholar 

  62. Tsukamoto, A. S., Grosschedl, R., Guzman, R. C., Parslow, T. & Varmus, H. E. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619–625 (1988).

    Article  CAS  Google Scholar 

  63. Kumar, M. P. et al. Analysis of single-cell RNA-seq identifies cell–cell communication associated with tumor characteristics. Cell Rep. 25, 1458–1468.e4 (2018).

    Article  CAS  Google Scholar 

  64. Broguiere, N. et al. Morphogenesis guided by 3D patterning of growth factors in biological matrices. Adv. Mater. 32, 1908299 (2020).

    Article  CAS  Google Scholar 

  65. Henke, E., Nandigama, R. & Ergün, S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front. Mol. Biosci. 6, 160 (2020).

    Article  Google Scholar 

  66. Nia, H. T., Munn, L. L. & Jain, R. K. Physical traits of cancer. Science 370, eaaz0868 (2020).

    Article  CAS  Google Scholar 

  67. Sheridan, C. Pancreatic cancer provides testbed for first mechanotherapeutics. Nat. Biotechnol. 37, 829–831 (2019).

    Article  CAS  Google Scholar 

  68. Weaver, V. M. et al. Β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2, 205–216 (2002).

    Article  CAS  Google Scholar 

  69. Kenny, P. A. et al. The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol. Oncol. 1, 84–96 (2007).

    Article  CAS  Google Scholar 

  70. Corning Matrigel Matrix: Frequently Asked Questions (Corning, 2019); https://www.corning.com/catalog/cls/documents/faqs/CLS-DL-CC-026.pdf

  71. Aisenbrey, E. A. & Murphy, W. L. Synthetic alternatives to Matrigel. Nat. Rev. Mater. 5, 539–551 (2020).

    Article  CAS  Google Scholar 

  72. Hughes, C. S., Postovit, L. M. & Lajoie, G. A. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10, 1886–1890 (2010).

    Article  CAS  Google Scholar 

  73. Acerbi, I. et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 7, 1120–1134 (2015).

    Article  CAS  Google Scholar 

  74. Slater, K., Partridge, J. & Nandivada, H. Tuning the Elastic Moduli of Corning Matrigel and Collagen I 3D Matrices by Varying the Protein Concentration (Corning, 2019); https://www.corning.com/catalog/cls/documents/application-notes/CLS-AC-AN-449.pdf

  75. Lu, P., Weaver, V. M. & Werb, Z. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406 (2012).

    Article  CAS  Google Scholar 

  76. Hapach, L. A., Vanderburgh, J. A., Miller, J. P. & Reinhart-King, C. A. Manipulation of in vitro collagen matrix architecture for scaffolds of improved physiological relevance. Phys. Biol. 12, 061002 (2015).

    Article  Google Scholar 

  77. Velez, D. O. et al. 3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry. Nat. Commun. 8, 1651 (2017).

    Article  CAS  Google Scholar 

  78. Liu, Z. & Vunjak-Novakovic, G. Modeling tumor microenvironments using custom-designed biomaterial scaffolds. Curr. Opin. Chem. Eng. 11, 94–105 (2016).

    Article  Google Scholar 

  79. Gu, L. & Mooney, D. J. Biomaterials and emerging anticancer therapeutics: engineering the microenvironment. Nat. Rev. Cancer 16, 56–66 (2016).

    Article  CAS  Google Scholar 

  80. Xiao, W. et al. Brain-mimetic 3D culture platforms allow investigation of cooperative effects of extracellular matrix features on therapeutic resistance in glioblastoma. Cancer Res. 78, 1358–1370 (2018).

    Article  CAS  Google Scholar 

  81. Kratochvil, M. J. et al. Engineered materials for organoid systems. Nat. Rev. Mater. 4, 606–622 (2019).

    Article  CAS  Google Scholar 

  82. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).

    Article  CAS  Google Scholar 

  83. Rezakhani, S., Gjorevski, N. & Lutolf, M. P. Low-defect thiol–Michael addition hydrogels as Matrigel substitutes for epithelial organoid derivation. Adv. Funct. Mater. 30, 2000761 (2020).

    Article  CAS  Google Scholar 

  84. Cruz-Acuña, R. et al. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat. Cell Biol. 19, 1326–1335 (2017).

    Article  Google Scholar 

  85. Hernandez-Gordillo, V. et al. Fully synthetic matrices for in vitro culture of primary human intestinal enteroids and endometrial organoids. Biomaterials 254, 120125 (2020).

    Article  CAS  Google Scholar 

  86. Chen, Y., Zhou, W., Roh, T., Estes, M. K. & Kaplan, D. L. In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS ONE 12, e0187880 (2017).

    Article  Google Scholar 

  87. Capeling, M. M. et al. Nonadhesive alginate hydrogels support growth of pluripotent stem cell-derived intestinal organoids. Stem Cell Rep. 12, 381–394 (2019).

    Article  CAS  Google Scholar 

  88. Broguiere, N. et al. Growth of epithelial organoids in a defined hydrogel. Adv. Mater. 30, e1801621 (2018).

    Article  Google Scholar 

  89. DiMarco, R. L., Dewi, R. E., Bernal, G., Kuo, C. & Heilshorn, S. C. Protein-engineered scaffolds for in vitro 3D culture of primary adult intestinal organoids. Biomater. Sci. 3, 1376–1385 (2015).

    Article  CAS  Google Scholar 

  90. Hunt, D. R. et al. Engineered matrices enable the culture of human patient-derived intestinal organoids. Adv. Sci. 8, 2004705 (2021).

    Article  CAS  Google Scholar 

  91. DeForest, C. A. & Tirrell, D. A. A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels. Nat. Mater. 14, 523–531 (2015).

    Article  CAS  Google Scholar 

  92. Stowers, R. S., Allen, S. C. & Suggs, L. J. Dynamic phototuning of 3D hydrogel stiffness. Proc. Natl Acad. Sci. USA 112, 1953–1958 (2015).

    Article  CAS  Google Scholar 

  93. Hushka, E. A., Yavitt, F. M., Brown, T. E., Dempsey, P. J. & Anseth, K. S. Relaxation of extracellular matrix forces directs crypt formation and architecture in intestinal organoids. Adv. Healthc. Mater. 9, 1901214 (2020).

    Article  CAS  Google Scholar 

  94. Brassard, J. A., Nikolaev, M., Hübscher, T., Hofer, M. & Lutolf, M. P. Recapitulating macro-scale tissue self-organization through organoid bioprinting. Nat. Mater. 20, 22–29 (2021).

    Article  CAS  Google Scholar 

  95. Krajina, B. A. et al. Microrheology reveals simultaneous cell-mediated matrix stiffening and fluidization that underlie breast cancer invasion. Sci. Adv. 7, eabe1969 (2021).

    Article  CAS  Google Scholar 

  96. 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  Google Scholar 

  97. Forbes, T. A. et al. Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. Am. J. Hum. Genet. 102, 816–831 (2018).

    Article  CAS  Google Scholar 

  98. Cruz, N. M. et al. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat. Mater. 16, 1112–1119 (2017).

    Article  CAS  Google Scholar 

  99. Linnemann, J. R. et al. Quantification of regenerative potential in primary human mammary epithelial cells. Development 142, 3239–3251 (2015).

    CAS  Google Scholar 

  100. Rocco, S. A. et al. Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids. Toxicol. Sci. 164, 592–602 (2018).

    Article  CAS  Google Scholar 

  101. Cha, J., Kang, S. G. & Kim, P. Strategies of mesenchymal invasion of patient-derived brain tumors: microenvironmental adaptation. Sci. Rep. 6, 24912 (2016).

    Article  CAS  Google Scholar 

  102. Wilkinson, D. C. et al. Development of a three-dimensional bioengineering technology to generate lung tissue for personalized disease modeling. Stem Cells Transl. Med. 6, 622–633 (2017).

    Article  Google Scholar 

  103. Ng, S. S. et al. Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly(ethylene glycol) scaffold. Biomaterials 182, 299–311 (2018).

    Article  CAS  Google Scholar 

  104. Rajasekar, S. et al. IFlowPlate—a customized 384-well plate for the culture of perfusable vascularized colon organoids. Adv. Mater. 32, 2002974 (2020).

    Article  CAS  Google Scholar 

  105. Lindborg, B. A. et al. Rapid induction of cerebral organoids from human induced pluripotent stem cells using a chemically defined hydrogel and defined cell culture medium. Stem Cells Transl. Med. 5, 970–979 (2016).

    Article  CAS  Google Scholar 

  106. Astashkina, A. I. et al. Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model. Biomaterials 35, 6323–6331 (2014).

    Article  CAS  Google Scholar 

  107. Bejoy, J. et al. Differential effects of heparin and hyaluronic acid on neural patterning of human induced pluripotent stem cells. ACS Biomater. Sci. Eng. 4, 4354–4366 (2018).

    Article  CAS  Google Scholar 

  108. Kaemmerer, E. et al. Gelatine methacrylamide-based hydrogels: an alternative three-dimensional cancer cell culture system. Acta Biomater. 10, 2551–2562 (2014).

    Article  CAS  Google Scholar 

  109. Zhang, Y. S. et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc. Natl Acad. Sci. USA 114, E2293–E2302 (2017).

    CAS  Google Scholar 

  110. Töpfer, E. et al. Bovine colon organoids: from 3D bioprinting to cryopreserved multi-well screening platforms. Toxicol. Vitr. 61, 104606 (2019).

    Article  Google Scholar 

  111. Baptista, P. M. et al. The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 53, 604–617 (2011).

    Article  CAS  Google Scholar 

  112. Giobbe, G. G. et al. Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture. Nat. Commun. 10, 5658 (2019).

    Article  Google Scholar 

  113. Dye, B. R. et al. In vitro generation of human pluripotent stem cell derived lung organoids. eLife 4, e05098 (2015).

    Article  Google Scholar 

  114. Zhu, Y. et al. A hollow fiber system for simple generation of human brain organoids. Integr. Biol. 9, 774–781 (2017).

    Article  CAS  Google Scholar 

  115. Geuens, T. et al. Thiol-ene cross-linked alginate hydrogel encapsulation modulates the extracellular matrix of kidney organoids by reducing abnormal type 1a1 collagen deposition. Biomaterials 275, 120976 (2021).

    Article  CAS  Google Scholar 

  116. Gupta, A. K. et al. Scaffolding kidney organoids on silk. J. Tissue Eng. Regen. Med. 13, 812–822 (2019).

    Article  CAS  Google Scholar 

  117. Curvello, R. et al. Engineered plant-based nanocellulose hydrogel for small intestinal organoid growth. Adv. Sci. 8, 2002135 (2020).

    Article  Google Scholar 

  118. Krüger, M. et al. Cellulose nanofibril hydrogel promotes hepatic differentiation of human liver organoids. Adv. Healthc. Mater. 9, e1901658 (2020).

    Article  Google Scholar 

  119. Nowak, M., Freudenberg, U., Tsurkan, M. V., Werner, C. & Levental, K. R. Modular GAG-matrices to promote mammary epithelial morphogenesis in vitro. Biomaterials 112, 20–30 (2017).

    Article  CAS  Google Scholar 

  120. Ma, Z. et al. Self-organizing human cardiac microchambers mediated by geometric confinement. Nat. Commun. 6, 7413 (2015).

    Article  CAS  Google Scholar 

  121. Sorrentino, G. et al. Mechano-modulatory synthetic niches for liver organoid derivation. Nat. Commun. 11, 3416 (2020).

    Article  CAS  Google Scholar 

  122. Greggio, C. et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140, 4452–4462 (2013).

    Article  CAS  Google Scholar 

  123. Hainline, K. M. et al. Self-assembling peptide gels for 3D prostate cancer spheroid culture. Macromol. Biosci. 19, 1800249 (2019).

    Article  Google Scholar 

  124. Fumagalli, A. et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 26, 569–578.e7 (2020).

    Article  CAS  Google Scholar 

  125. Ylä-Outinen, L., Joki, T., Varjola, M., Skottman, H. & Narkilahti, S. Three-dimensional growth matrix for human embryonic stem cell-derived neuronal cells. J. Tissue Eng. Regen. Med. 8, 186–194 (2014).

    Article  Google Scholar 

  126. Lancaster, M. A. et al. Guided self-organization and cortical plate formation in human brain organoids. Nat. Biotechnol. 35, 659–666 (2017).

    Article  CAS  Google Scholar 

  127. 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  Google Scholar 

  128. Nayak, B., Balachander, G. M., Manjunath, S., Rangarajan, A. & Chatterjee, K. Tissue mimetic 3D scaffold for breast tumor-derived organoid culture toward personalized chemotherapy. Colloids Surf. B 180, 334–343 (2019).

    Article  CAS  Google Scholar 

  129. Garreta, E. et al. Fine tuning the extracellular environment accelerates the derivation of kidney organoids from human pluripotent stem cells. Nat. Mater. 18, 397–405 (2019).

    Article  CAS  Google Scholar 

  130. Ye, S. et al. A chemically defined hydrogel for human liver organoid culture. Adv. Funct. Mater. 30, 2000893 (2020).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  132. Gillet, J. P., Varma, S. & Gottesman, M. M. The clinical relevance of cancer cell lines. J. Natl Cancer Inst. 105, 452–458 (2013).

    Article  CAS  Google Scholar 

  133. Lai, Y. et al. Current status and perspectives of patient-derived xenograft models in cancer research. J. Hematol. Oncol. 10, 106 (2017).

    Article  Google Scholar 

  134. Day, C. P., Merlino, G. & Van Dyke, T. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell 163, 39–53 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  136. Wong, C. H., Siah, K. W. & Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2019).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  138. Zafra, M. P. et al. Optimized base editors enable efficient editing in cells, organoids and mice. Nat. Biotechnol. 36, 888–896 (2018).

    Article  CAS  Google Scholar 

  139. 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  Google Scholar 

Download references

Acknowledgements

We thank T. M. Lozanoski, J. G. Roth and R. E. Dewi for insightful conversations and editing of the manuscript. B.L.L. acknowledges financial support from the Stanford Bio-X Bowes Graduate Fellowship. R.A.S. acknowledges financial support from the National Institutes of Health Training Grant in Biotechnology (T32-GM008412) and the Stanford Lieberman Fellowship. This work was supported by funding from the National Institutes of Health (R01 EB027171, U01 DK085527) and the National Science Foundation (NSF CBET 2033302). The work of the Lutolf laboratory in the area of cancer organoid biology and technology is supported by the Personalized Health and Related Technologies Initiative from the ETH Board, the Swiss 3R Competence Centre (https://swiss3rcc.org) and the École Polytechnique Fédérale de Lausanne (EPFL).

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Authors and Affiliations

  1. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Bauer L. LeSavage

  2. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

    Riley A. Suhar & Sarah C. Heilshorn

  3. Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Nicolas Broguiere & Matthias P. Lutolf

  4. Institute of Chemical Sciences and Engineering, School of Basic Science, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Nicolas Broguiere & Matthias P. Lutolf

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  1. Bauer L. LeSavage
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  2. Riley A. Suhar
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  3. Nicolas Broguiere
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  4. Matthias P. Lutolf
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  5. Sarah C. Heilshorn
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Contributions

B.L.L. and S.C.H. conceived the Review. B.L.L. wrote the Review. R.A.S., B.L.L. and N.B. conceived and illustrated the figures and table. B.L.L., R.A.S., N.B., M.P.L. and S.C.H. edited the Review. All authors read and approved the final manuscript contents.

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Correspondence to Sarah C. Heilshorn.

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The authors declare no competing interests.

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Peer review information Nature Materials thanks Claudia Fischbach, Kai Kretzschmar and Toshiro Sato for their contribution to the peer review of this work.

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LeSavage, B.L., Suhar, R.A., Broguiere, N. et al. Next-generation cancer organoids. Nat. Mater. 21, 143–159 (2022). https://doi.org/10.1038/s41563-021-01057-5

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