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• W2419031570 abstract "Organoid technologies have significant potential as effective patient avatars. Fujii et al., 2016Fujii M. Shimokawa M. Date S. Takano A. Matano M. Nanki K. Ohta Y. Toshimitsu K. Nakazato Y. Kawasaki K. et al.Cell Stem Cell. 2016; 18 (this issue): 827-838Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar and van de Wetering et al., 2015van de Wetering M. Francies H.E. Francis J.M. Bounova G. Iorio F. Pronk A. van Houdt W. van Gorp J. Taylor-Weiner A. Kester L. et al.Cell. 2015; 161: 933-945Abstract Full Text Full Text PDF PubMed Scopus (1350) Google Scholar derive biobanks of colorectal tumor and matching normal organoids and identify associations between tumor subtype, oncogenic drivers, gene-drug interactions, and varying niche requirements for tumor organoid growth, engraftment, and metastasis. Organoid technologies have significant potential as effective patient avatars. Fujii et al., 2016Fujii M. Shimokawa M. Date S. Takano A. Matano M. Nanki K. Ohta Y. Toshimitsu K. Nakazato Y. Kawasaki K. et al.Cell Stem Cell. 2016; 18 (this issue): 827-838Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar and van de Wetering et al., 2015van de Wetering M. Francies H.E. Francis J.M. Bounova G. Iorio F. Pronk A. van Houdt W. van Gorp J. Taylor-Weiner A. Kester L. et al.Cell. 2015; 161: 933-945Abstract Full Text Full Text PDF PubMed Scopus (1350) Google Scholar derive biobanks of colorectal tumor and matching normal organoids and identify associations between tumor subtype, oncogenic drivers, gene-drug interactions, and varying niche requirements for tumor organoid growth, engraftment, and metastasis. Three-dimensional organoids have emerged as promising experimental tools that may reflect the natural state of organs better than traditional cell culture models. Improved understanding of niche factor requirements led to the development of defined conditions for the growth and expansion of intestinal stem cells as 3D intestinal organoids (Sato et al., 2009Sato T. Vries R.G. Snippert H.J. van de Wetering M. Barker N. Stange D.E. van Es J.H. Abo A. Kujala P. Peters P.J. Clevers H. Nature. 2009; 459: 262-265Crossref PubMed Scopus (4124) Google Scholar). These 3D intestinal organoids, also called enteroids, retain a stem cell hierarchical organization, wherein self-renewing stem cells continuously produce diverse differentiated cell types. An explosion of studies have used enteroids to explore questions regarding stemness, physiology, and oncogenic transformation (Sato and Clevers, 2013Sato T. Clevers H. Science. 2013; 340: 1190-1194Crossref PubMed Scopus (774) Google Scholar, Zachos et al., 2016Zachos N.C. Kovbasnjuk O. Foulke-Abel J. In J. Blutt S.E. de Jonge H.R. Estes M.K. Donowitz M. J. Biol. Chem. 2016; 291: 3759-3766Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Recently in Cell and now in Cell Stem Cell, the Clevers (van de Wetering et al., 2015van de Wetering M. Francies H.E. Francis J.M. Bounova G. Iorio F. Pronk A. van Houdt W. van Gorp J. Taylor-Weiner A. Kester L. et al.Cell. 2015; 161: 933-945Abstract Full Text Full Text PDF PubMed Scopus (1350) Google Scholar) and Sato (Fujii et al., 2016Fujii M. Shimokawa M. Date S. Takano A. Matano M. Nanki K. Ohta Y. Toshimitsu K. Nakazato Y. Kawasaki K. et al.Cell Stem Cell. 2016; 18 (this issue): 827-838Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar) groups derive and characterize libraries of organoids from human colorectal tumors, describing effects of parameters such as mutational status and niche requirements on tumor growth, metastasic potential, and drug response. Three-dimensional cancer cell cultures have been previously used to gain insight into the growth and metastatic process in several cancers, but have primarily been derived from cell lines after extensive passaging as monolayers (Tanner and Gottesman, 2015Tanner K. Gottesman M.M. Sci. Transl. Med. 2015; 7: 283ps9Crossref PubMed Scopus (64) Google Scholar). Another approach has been to generate tumor spheroids from fresh tumor specimens. This strategy was used to propagate cancer stem cells in colorectal and other cancers (Ricci-Vitiani et al., 2007Ricci-Vitiani L. Lombardi D.G. Pilozzi E. Biffoni M. Todaro M. Peschle C. De Maria R. Nature. 2007; 445: 111-115Crossref PubMed Scopus (3401) Google Scholar, Singh et al., 2003Singh S.K. Clarke I.D. Terasaki M. Bonn V.E. Hawkins C. Squire J. Dirks P.B. Cancer Res. 2003; 63: 5821-5828PubMed Google Scholar). While the tumor spheroid approach has been highly useful in evaluating the tumor-initiating properties of purified cell populations, the ability to grow tumor spheroids from a broad range of cancer subtypes has been somewhat limited, and it is unclear how well the growth conditions for tumor spheroids reflect endogenous cancer niches. More recently, the conditions for growth of 3D intestinal organoids were adapted for growth of colorectal cancers and pre-cancerous polyps (Sato et al., 2011Sato T. Stange D.E. Ferrante M. Vries R.G.J. Van Es J.H. Van den Brink S. Van Houdt W.J. Pronk A. Van Gorp J. Siersema P.D. Clevers H. Gastroenterology. 2011; 141: 1762-1772Abstract Full Text Full Text PDF PubMed Scopus (2095) Google Scholar). A recent study used this technique to derive 22 colorectal tumor organoids and normal organoids from adjacent non-cancerous tissue, with a high rate of establishing organoids from these tumors (van de Wetering et al., 2015van de Wetering M. Francies H.E. Francis J.M. Bounova G. Iorio F. Pronk A. van Houdt W. van Gorp J. Taylor-Weiner A. Kester L. et al.Cell. 2015; 161: 933-945Abstract Full Text Full Text PDF PubMed Scopus (1350) Google Scholar). In the current study, Fujii et al., 2016Fujii M. Shimokawa M. Date S. Takano A. Matano M. Nanki K. Ohta Y. Toshimitsu K. Nakazato Y. Kawasaki K. et al.Cell Stem Cell. 2016; 18 (this issue): 827-838Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar improve on this technique to derive a biobank of 55 colorectal tumor organoid lines and 41 matching normal colorectal organoids. Importantly, they used an array of culture conditions for every tumor to achieve growth of organoids from nearly 100% of tumor specimens—a significant improvement over spheroid and primary monolayer methods for cancer cell growth. They were also able to generate tumor organoids from rectal cancer biopsies and from several rare colorectal tumors, including neuroendocrine cancers and serrated adenomas. Both groups showed that colorectal tumor organoids retained characteristic genetic and histopathologic features of the originating tumor, and expression profiling allowed unsupervised clustering of the organoids into groups aligned with genetic and pathologic classifications. van de Wetering et al. used their colon tumor organoids to perform a focused screen for drugs that impaired cell growth and correlated their results with genotypic characterization of the tumor organoids. They found varying responsesto drugs across the colon tumor organoids and identified predicted genotype-drug interactions, such as sensitivity to the MDM2-inhibitor Nutlin-3a in p53 inactivated tumor organoids, and sensitivity to anti-EGFR treatment in tumor organoids lacking RAS mutations. This proof-of-concept study demonstrates the feasibility of high-throughput drug screening in tumor organoids and brings the promise of personalized cancer treatment closer to fruition for colon cancer patients. Fujii et al. used their colorectal tumor organoids to evaluate the niche factor requirements for each tumor organoid. They identified expected associations wherein oncogenic pathway mutations obviated the requirement for niche factors. For example, most tumor organoids had acquired mutations in the Wnt and TGF-beta signaling pathways and therefore did not require Wnt pathway stimulation or TGF-beta pathway inhibition. Interestingly, Fujii et al. found that organoids that required EGF for growth also frequently required inhibition of p38, which was associated with ligand-mediated EGFR internalization. They also found a subset of KRAS mutant tumor organoids that required EGF for growth, suggesting that anti-EGFR therapy may provide some benefit to those patients. Fujii et al. went on to establish renal subcapsular xenografts for 21 colorectal cancer organoids, with a remarkable 100% efficiency. They found that the ability of tumor organoids to grow in the absence of niche factors correlated with xenograft size, suggesting an association between niche independence and growth rate. Finally, they observed that tumor organoids derived from liver metastases showed greater metastatic capacity in xenografts compared to the matched primary tumor-derived organoid, despite the mutational and gene expression signatures of these organoid pairs being indistinguishable. These results suggest that while the major oncogenic driver mutations confer a selective advantage and improved growth potential to colorectal tumors, metastatic potential may be associated with non-mutational events or with very subtle changes to the cancer cells. Patient-derived tumor xenografts (PDXs), in which tumor tissue is engrafted into immunocompromised mice, have become a gold standard in the field and are thought to recapitulate the biology of the original tumor in an experimentally tractable system (Aparicio et al., 2015Aparicio S. Hidalgo M. Kung A.L. Nat. Rev. Cancer. 2015; 15: 311-316Crossref PubMed Scopus (256) Google Scholar). However, widespread use of PDX models as patient avatars for preclinical testing is hampered by the labor-intensive nature of generating new PDX lines, the long time required to expand new PDX lines for experimental manipulation, and the limited efficiency of forming new PDX lines from tumor tissues. Tumor organoids may solve each of these issues. Additionally, xenografts could be derived from all malignant tumor organoids, demonstrating an efficient route from organoid to xenograft. Direct comparisons of tumor organoids, organoid-derived xenografts, PDXs, and tumor spheroids are now needed to assess the relative advantages of each system. Further refinements to tumor organoid protocols will enable deeper insights into cancer biology. Tumor organoids are composed exclusively of tumor cells and lack cancer-associated stromal and immune components that have important roles in disease pathogenesis. Adding additional cellular and noncellular components to the tumor organoid cultures multiplies their complexity and has not yet been applied in the setting of colorectal cancer-derived tumor organoids. Another potential limitation of the tumor organoid system is that competition among different clones within the cultures selects for subclones that dominate the cultures within a month. Thus, tumor organoids lose the heterogeneity of the original tumor over time. Single-cell clonal cultures of tumor organoids will provide insight into functional heterogeneity within the tumor and may predict the emergence of drug-resistant clones during treatment of cancer patients. Together, such studies would build upon the findings of van de Wetering et al. and Fujii et al., potentially leading to the development of highly sophisticated cancer models and personalized therapeutic regimens. Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patientsvan de Wetering et al.CellMay 07, 2015In Brief3D organoid cultures derived from healthy and tumor tissue from colorectal cancer patients are used for a high throughput drug screen to identify gene-drug associations that may facilitate personalized therapy. Full-Text PDF Open ArchiveA Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during TumorigenesisFujii et al.Cell Stem CellMay 19, 2016In BriefFujii et al. generated a comprehensive organoid library from colorectal cancer patients. Each organoid line was characterized by gene expression and as xenografts recapitulating the original clinical phenotype. By optimizing niche factor requirements and derivation efficiency, they were able to encompass a range of clinical stages and rare subtypes and reveal that niche-independent growth is progressively associated with the adenoma-carcinoma transition. Full-Text PDF Open Archive" @default.
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• W2419031570 title "Tumor Organoids Fill the Niche" @default.
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• W2419031570 doi "https://doi.org/10.1016/j.stem.2016.05.020" @default.
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