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

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.

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Acknowledgements

The authors acknowledge the experimental support of Dr. Chantal Humblet, Mrs. Alice Marquet (GIGA-histology platform, ULg), Mr. Vincent Hennequière, Mrs. Naima Maloujahmoum (Metastasis Research Laboratory), Mrs. Yezza Ben Salah (Tumor Microenvironment and Resistance to Treatment Lab, IRCM), Mr. Nicolas Passon (CMMI) and Mrs. Mari-Aline Laute (CMMI). The authors are thankful to Dr. Stéphanie Gofflot (Biobank, University Hospital Liege) for providing patient material as well as the Cyclotron Unit of Erasme Hospital (Brussels, Belgium) for providing [18F]-FDG. Prof. Robert N. Muller (CMMI, Director of international partnerships) is thanked for his scientific input and support. Mr. Mathieu Roch (CMMI) is thanked for tumor volume measurements on MR images.This work was supported with grants from the University of Liège, National Fund for Scientific Research (FNRS) and Gunma University (GIAR Research Program for Omics-Based Medical Science). The CMMI is supported by the European Regional Development Fund (ERDF), the Walloon Region, the Fondation ULB, the Fonds Erasme and the “Association Vinçotte Nuclear” (AVN). GD is supported by the ERDF and the Walloon Region. Akeila Bellahcène is a Research Director at the FNRS. AT is a senior research fellow of the French National Institute of Health and Medical Research (INSERM) and is supported by LabEx MabImprove Starting Grant. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Andrei Turtoi.

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Vincent Castronovo and Andrei Turtoi contributed equally to this work.

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Blomme, A., Van Simaeys, G., Doumont, G. et al. Murine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases. Oncogene 37, 1237–1250 (2018). https://doi.org/10.1038/s41388-017-0018-x

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