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Article Dans Une Revue Oncogene Année : 2018

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

Arnaud Blomme
  • Fonction : Auteur
Gaetan van Simaeys
  • Fonction : Auteur
Gilles Doumont
  • Fonction : Auteur
Brunella Costanza
  • Fonction : Auteur
Justine Bellier
  • Fonction : Auteur
Yukihiro Otaka
  • Fonction : Auteur
Félicie Sherer
  • Fonction : Auteur
Pierre Lovinfosse
  • Fonction : Auteur
Sébastien Boutry
  • Fonction : Auteur
Ana Perez Palacios
  • Fonction : Auteur
Edwin de Pauw
  • Fonction : Auteur
Touko Hirano
  • Fonction : Auteur
Takehiko Yokobori
  • Fonction : Auteur
Roland Hustinx
  • Fonction : Auteur
Akeila Bellahcene
  • Fonction : Auteur
Philippe Delvenne
  • Fonction : Auteur
Olivier Detry
  • Fonction : Auteur
Serge Goldman
  • Fonction : Auteur
Masahiko Nishiyama
  • Fonction : Auteur
Vincent Castronovo
  • Fonction : Auteur

Résumé

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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Dates et versions

hal-02284973 , version 1 (12-09-2019)

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Citer

Arnaud Blomme, Gaetan van Simaeys, Gilles Doumont, Brunella Costanza, Justine Bellier, et al.. Murine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases. Oncogene, 2018, 37 (9), pp.1237-1250. ⟨10.1038/s41388-017-0018-x⟩. ⟨hal-02284973⟩
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