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Oncogene. 2018 Mar;37(9):1237-1250. doi: 10.1038/s41388-017-0018-x. Epub 2017 Dec 15.

Murine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases.

Author information

1
Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
2
Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
3
Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Charleroi (Gosselies), Brussels, Belgium.
4
Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
5
Nuclear Medicine and Oncological Imaging Division, Medical Physics Department, Liège University Hospital, Liège, Belgium.
6
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, Mons, Belgium.
7
Center for Microscopy and Molecular Imaging, Université de Mons (UMONS), Charleroi (Gosselies), Belgium.
8
Mass Spectrometry Laboratory, University of Liège, Liège, Belgium.
9
Laboratory for Analytical Instruments, Gunma University Graduate School of Medicine, Gunma, Japan.
10
Department of Pathology, University Hospital, University of Liège, Liège, Belgium.
11
Department of Abdominal Surgery, University Hospital, University of Liège, Liège, Belgium.
12
Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium. andrei.turtoi@inserm.fr.
13
Tumor Microenvironment and Resistance to Treatment Lab, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. andrei.turtoi@inserm.fr.
14
Institut du Cancer, Montpellier, Montpellier, France. andrei.turtoi@inserm.fr.
15
INSERM, U1194, Montpellier, France. andrei.turtoi@inserm.fr.
16
Université, Montpellier, Montpellier, France. andrei.turtoi@inserm.fr.

Abstract

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations. Metabolic signatures of cancer cells and stroma were measured separately by MALDI-imaging, while metabolite changes in entire tumors were quantified using mass spectrometry approach. Measurement of glucose metabolism was also conducted in vivo using [18F]-fluorodeoxyglucose (FDG) and positron emission tomography (PET). In CRC/CRC-LM PDX model, human stroma was entirely replaced at the second generation. Despite this change, MALDI-imaging demonstrated that the metabolic profiles of both stromal and cancer cells remained stable for at least four generations in comparison to the original patient material. On the tumor level, profiles of 86 water-soluble metabolites as well as 93 lipid mediators underlined the functional stability of the PDX model. In vivo PET measurement of glucose uptake (reflecting tumor glucose metabolism) supported the ex vivo observations. Our data show for the first time that CRC/CRC-LM PDX model maintains the functional stability at the metabolic level despite the early replacement of the human stroma by murine cells. The findings demonstrate that human cancer cells actively educate murine stromal cells during PDX development to adopt the human-like phenotype.

PMID:
29242606
DOI:
10.1038/s41388-017-0018-x

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