Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells

Simon C Body ,Gaël Roué,Patricia Pérez-Galán,Pablo Menéndez,Ramón Mangues,Régis Lavigne,Anna Esteve-Arenys,Sophie Bustany,B Marcq ,Fabrice Jardin,Guergana Tchakarska,Clara Recasens-Zorzo,Isolda Casanova,Emmanuelle Com,Anna Vidal-Crespo,Alejandra Sanjuán-Pla ,Oliver Weigert,Vanina Rodríguez ,Hadjer Miloudi,Alexandra Moros,Jean‐Michel Picquenot ,Brigitte Sola

doi:10.1038/s41598-017-14222-1

Abstract

Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.

Highlights

Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression
We confirmed the preferential cytoplasmic localisation of cyclin D1 in JeKo1 and Z138 cells, in which this ratio exceeded 1. We investigated whether such heterogeneity in subcellular distribution was observed in primary cells from MCL patients
Slides were counterstained with DAPI and analysed by confocal microscopy (x180, magnification). (B) JeKo1 and Z138 cells cells were treated with vehicle or KPT-330 (300 nM for 4 h) and used to seed the upper chamber of Transwell inserts

Summary

Introduction

Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. We showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Depending on its subcellular distribution (nuclear, cytoplasmic, at the outer mitochondrial membrane) and its partners (transcription factors, chromatin-modifying enzymes, cytosolic proteins), cyclin D1 can regulate DNA damage response[3,4], chromosome duplication and stability[5,6], senescence[7], mitochondrial function[8,9] and migration[10,11,12], all key biological processes for cancer initiation and maintenance. The mean values are reported in the table. (C) Cyclin D1 staining of two biopsy specimens from MCL patients (x20, magnification)

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Results

Conclusion