Cell growth in aggregates determines gene expression, proliferation, survival, chemoresistance, and sensitivity to immune effectors in follicular lymphoma.

Pauline Gravelle 1, * Christine Jean 2, 3 Julien Familiades 2, 3, 4 Emilie Decaup 2, 3, 4, 5 Amandine Blanc 2, 3, 4 Christine Bezombes-Cagnac 6 Camille Laurent 2, 7 Ariel Savina 2, 5 Jean-Jacques Fournié 2, 3, 4 Guy Laurent 2, 3, 4, 8
* Auteur correspondant
1 Jean Jacques Fournié
CRCT - Centre de Recherche en Cancérologie de Toulouse, Consortium pour l'Accélération de l'Innovation et de son Transfert dans le Domaine du Lymphome, CRCT - Centre de recherche en cancérologie de Toulouse
6 Jean-Jacques Fournié
CRCT - Centre de Recherche en Cancérologie de Toulouse, Consortium pour l'Accélération de l'Innovation et de son Transfert dans le Domaine du Lymphome, CRCT - Centre de recherche en cancérologie de Toulouse
Abstract : Lymphomas grow as dense aggregates in patients, but whether this spatial organization affects lymphoma cell biology is unknown. We grew follicular lymphoma (FL) cells in vitro as multicellular aggregates of lymphoma cells to investigate this question. Gene expression analysis revealed that 612 genes were differentially expressed when cells grew in multicellular aggregates of lymphoma cells rather than in suspension. These genes correspond to several GO biological processes, such as hypoxia, activation of NF-κB pathway, and negative regulation of cell cycle, a gene signature also found in the transcriptomes from FL biopsies. Pimonidazole staining, HIF-1A accumulation, and VEGFA release confirmed that cells in multicellular aggregates of lymphoma cells actually respond to hypoxia. In adaptation to such conditions, they also displayed an activated NF-κB pathway and a quiescent status far more frequently than in suspension. When cultured in three dimensions, FL cells display resistance to doxorubicin and bendamustine, two drugs largely used in FL therapy, compared to FL cultured in suspension. Finally, multicellular aggregates of lymphoma cells were also found to be less sensitive to purified natural killer cells. To conclude, our study shows that in FL, spatial organization results in dramatic changes in FL biology, including gene expression, proliferation, drug resistance, and immune escape.
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Article dans une revue
American Journal of Pathology, American Society for Investigative Pathology, 2014, 184 (1), pp.282-95. 〈10.1016/j.ajpath.2013.09.018〉
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Soumis le : lundi 18 novembre 2013 - 18:55:03
Dernière modification le : jeudi 11 janvier 2018 - 06:26:41
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Pauline Gravelle, Christine Jean, Julien Familiades, Emilie Decaup, Amandine Blanc, et al.. Cell growth in aggregates determines gene expression, proliferation, survival, chemoresistance, and sensitivity to immune effectors in follicular lymphoma.. American Journal of Pathology, American Society for Investigative Pathology, 2014, 184 (1), pp.282-95. 〈10.1016/j.ajpath.2013.09.018〉. 〈inserm-00905913〉

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