Capturing complex tumour biology in vitro: histological and molecular characterisation of precision cut slices

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Abstract

Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1α. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means.

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Most cited references 15

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Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

Adam S Crystal, Alice Shaw, Lecia V. Sequist … (2014)

Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

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Cancer cell lines for drug discovery and development.

Edward Wilding, W Bodmer (2014)

Despite the millions of dollars spent on target validation and drug optimization in preclinical models, most therapies still fail in phase III clinical trials. Our current model systems, or the way we interpret data from them, clearly do not have sufficient clinical predictive power. Current opinion suggests that this is because the cell lines and xenografts that are commonly used are inadequate models that do not effectively mimic and predict human responses. This has become such a widespread belief that it approaches dogma in the field of drug discovery and optimization and has spurred a surge in studies devoted to the development of more sophisticated animal models such as orthotopic patient-derived xenografts in an attempt to obtain more accurate estimates of whether particular cancers will respond to given treatments. Here, we explore the evidence that has led to the move away from the use of in vitro cell lines and toward various forms of xenograft models for drug screening and development. We review some of the pros and cons of each model and give an overview of ways in which the use of cell lines could be modified to improve the predictive capacity of this well-defined model. ©2014 AACR.

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Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors.

Massimo Loda, Giorgia Zadra, Valentina Vaira … (2010)

Predicting drug response in cancer patients remains a major challenge in the clinic. We have perfected an ex vivo, reproducible, rapid and personalized culture method to investigate antitumoral pharmacological properties that preserves the original cancer microenvironment. Response to signal transduction inhibitors in cancer is determined not only by properties of the drug target but also by mutations in other signaling molecules and the tumor microenvironment. As a proof of concept, we, therefore, focused on the PI3K/Akt signaling pathway, because it plays a prominent role in cancer and its activity is affected by epithelial-stromal interactions. Our results show that this culture model preserves tissue 3D architecture, cell viability, pathway activity, and global gene-expression profiles up to 5 days ex vivo. In addition, we show pathway modulation in tumor cells resulting from pharmacologic intervention in ex vivo culture. This technology may have a significant impact on patient selection for clinical trials and in predicting response to small-molecule inhibitor therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 09 December 2015

Publication date Collection: 2015

Volume: 5

Electronic Location Identifier: 17187

Affiliations

[1 ]Oncology iMed, Bioscience, AstraZeneca , Alderley Park, Macclesfield, SK10 4TG, United Kingdom

[2 ]Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Auerbachstrasse 112, 70376 Stuttgart, Germany

[3 ]FIMM, University of Helsinki ; Helsinki, Finland

[4 ]Department of Urology, Erasmus MC Rotterdam , PO Box 2040, 3000 CA Rotterdam, The Netherlands

[5 ]Institute of Computer Science, University of Tartu , J. Liivi 2, 50409, Tartu, Estonia

[6 ]Oncotest GmbH , Am Flughafen 12-14, 79108 Freiburg, Germany

[7 ]Institut de Recherches Servier c/o 126 boulevard Pereire , 75017 Paris, France

Author notes

[a ] john.hickman.part@ 123456servier.com

[b ] Heiko.vanderKuip@ 123456kp-stuttgart.de

[*]

These authors contributed equally to this work.

[†]

These authors jointly supervised this work

Article

Publisher Item ID: srep17187

DOI: 10.1038/srep17187

PMC ID: 4673528

PubMed ID: 26647838

SO-VID: 80650859-9132-4ed4-bb57-82494b05c05e

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Capturing complex tumour biology in vitro: histological and molecular characterisation of precision cut slices

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Abstract

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Vector Biology

Most cited references 15

Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

Cancer cell lines for drug discovery and development.

Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors.

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