The applications of PDTXs have been rapidly expanding, from studying biological processes to predicting the therapeutic response of patient samples.68,69 Unlike cell line xenografts where cultured cell lines are injected into immune-deficient mice, PDTXs are implanted tumor fragments taken from biopsy, maintaining key features of the tumor lost in two-dimensional (2D) culturing such as stroma, architecture, and heterogeneity. Preserving these qualities has allowed for accurate prediction of therapeutic sensitivities in numerous other cancers.70–72 Recently, multiple groups demonstrated successful PDTX models of CCA. A KRAS-mutant iCCA model was generated and shown to retain many features of the original tumor, including immunoreactivity and miRNA expression.73 Another group showed an IDH1-mutant PDTX displayed sensitivity to dasatinib, a multi-tyrosine kinase inhibitor shown to have efficacy on IDH1-mutant iCCA cells in vitro.74 Similarly, two PDTX models of iCCA were treated with an FGFR inhibitor, and the YAP-driven model displayed significantly reduced growth with treatment, supporting the group’s in vitro finding of a feed-forward loop between YAP and FGFR signaling.61 Some key limitations nevertheless exist for PDTX models. First, there is substantial variability in the success rate for creating PDTXs both among different cancers as well as between laboratories. Relatedly, the tumors that do successfully take in mice likely represent only the highly aggressive tumors. Finally, extensive time is required for the development of PDTXs, up to several months for the establishment of the primary graft, which is an especially important factor if being used to predict therapeutic response of a patient’s tumor.
A growing interest has developed regarding the utility of “organoid” models, a culture system in which cells are grown in a three-dimensional matrix and organize into epithelial-like structures that resemble the tissue of origin.75–77 Although liver cancer models remain to be adapted for this system, organoids have shown promise in a related gastrointestinal malignancy, pancreatic cancer. For example, one group fully characterized organoids derived from both normal, premalignant, and malignant pancreatic tissue from murine and human sources, demonstrating that organoids display morphological features and express markers that reflect the disease stage. Furthermore, orthotopic transplantation of these organoids fully recapitulates the disease spectrum. In addition to more closely resembling the native environment of the cells, a distinct advantage of organoids over 2D culture methods is the ability to retain more heterogeneity under these conditions due to the minimal selective pressure. It is also possible that this system may also more readily support growth of stroma to more closely recapitulate the native environment. Finally, a key advantage is that organoids can be prepared from tissue biopsies with relative ease and within a short time frame, such that therapeutic testing can be evaluated on organoids in parallel with the patient’s treatment. These properties suggest that there is significant application for personalized medicine. Thus, it remains to be determined how predictive organoids are for therapeutic responses.
Models of iCCA have progressed significantly over the past decade. Recent genomic advancements have enabled genetic characterization of hepatic malignancies and have fueled the rapid development of sophisticated animal models, from conditional GEMMs to refined somatic gene-editing tools. These advanced systems will enable a more thorough understanding of the development and progression of the disease and will provide flexible platforms for the evaluation of new treatments in a precise manner.
The authors report no conflicts of interest in this work.
Margaret A. Hill,1,2,* William B. Alexander,1,2,* Aram F. Hezel1,2
1Department of Biomedical Genetics, 2Department of Medicine, Hematology/Oncology, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
*These authors contributed equally to this work.
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Source: Gastrointestinal Cancer: Targets and Therapy.
Originally published February 19, 2018.