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      Patient-derived induced pluripotent stem cells in cancer research and precision oncology

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      Author(s): 1 , 2 , 3 , 4
      Publication date PMC-release:
      Journal: Nature medicine

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          Abstract

          Together with recent advances in the processing and culture of human tissue, bioengineering, xenotransplantation and genome editing, Induced pluripotent stem cells (iPSCs) present a range of new opportunities for the study of human cancer. Here we discuss the main advantages and limitations of iPSC modeling, and how the method intersects with other patient-derived models of cancer, such as organoids, organson-chips and patient-derived xenografts (PDXs). We highlight the opportunities that iPSC models can provide beyond those offered by existing systems and animal models and present current challenges and crucial areas for future improvements toward wider adoption of this technology.

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          Evolution of the cancer stem cell model.

          Antonija Kreso, John E. Dick (2014)
          Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. We offer an approach to integrating CSCs and cancer genetic data that will guide the field in interpreting past observations and designing future studies. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Organoid cultures derived from patients with advanced prostate cancer.

            Dong Gao, Ian Vela, Andrea Sboner … (2014)
            The lack of in vitro prostate cancer models that recapitulate the diversity of human prostate cancer has hampered progress in understanding disease pathogenesis and therapy response. Using a 3D organoid system, we report success in long-term culture of prostate cancer from biopsy specimens and circulating tumor cells. The first seven fully characterized organoid lines recapitulate the molecular diversity of prostate cancer subtypes, including TMPRSS2-ERG fusion, SPOP mutation, SPINK1 overexpression, and CHD1 loss. Whole-exome sequencing shows a low mutational burden, consistent with genomics studies, but with mutations in FOXA1 and PIK3R1, as well as in DNA repair and chromatin modifier pathways that have been reported in advanced disease. Loss of p53 and RB tumor suppressor pathway function are the most common feature shared across the organoid lines. The methodology described here should enable the generation of a large repertoire of patient-derived prostate cancer lines amenable to genetic and pharmacologic studies. Copyright © 2014 Elsevier Inc. All rights reserved.
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              In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.

              Marius Wernig, Alexander Meissner, Ruth Foreman … (2007)
              Nuclear transplantation can reprogramme a somatic genome back into an embryonic epigenetic state, and the reprogrammed nucleus can create a cloned animal or produce pluripotent embryonic stem cells. One potential use of the nuclear cloning approach is the derivation of 'customized' embryonic stem (ES) cells for patient-specific cell treatment, but technical and ethical considerations impede the therapeutic application of this technology. Reprogramming of fibroblasts to a pluripotent state can be induced in vitro through ectopic expression of the four transcription factors Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. Here we show that DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells. Notably, the cells-derived from mouse fibroblasts-can form viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts. Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.
              Article 0 comments Cited 529 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 6 January 2017
                Publication date (Print): 06 December 2016
                Publication date PMC-release: 06 December 2017
                Volume: 22
                Issue: 12
                Pages: 1392-1401
                Affiliations
                [1 ]Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [2 ]The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [3 ]The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [4 ]Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                Author notes
                Correspondence should be addressed to E.P.P. ( eirini.papapetrou@ 123456mssm.edu )
                Article
                Accession ID: PMC5233709 Pmcid ID: PMC5233709 Pmc-uid ID: 5233709 Manuscript ID: nihpa840731
                DOI: 10.1038/nm.4238
                PMC ID: 5233709
                PubMed ID: 27923030
                SO-VID: 28c9b4d7-6981-4cce-8a9c-021a02d4bf1e
                License:

                Reprints and permissions information is available online at http://www.nature.com/reprints/index.html.

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