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

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.

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

“…These findings are in line with a number of reports that Ccnd1 functionally interacts with cytoplasmic targets involved in the regulation of cell adhesion and invasion, such as filamin A, pacsin, Rgl2 and Pxn . Also, cytoplasmic Ccnd1 has been found at the invasive fronts of solid tumors and the invasive blastoid variant of mantle cell lymphoma , suggesting an important role of cytoplasmic Ccnd1 in tumor invasion. Moreover, accumulation of membrane Ccnd1 increases the metastatic potential of endometrial tumor cells in a lung metastasis mouse model .…”

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…Cyclin D1 activates cyclin‐dependent kinases 4 and 6 which in turn phosphorylate and inactivate Rb (tumor suppressor gene) and promote G1 to the S phase, leading to rapid cell proliferation. Enhanced cyclin D1 effect in MCL is largely attributed to t(11;14) and the location of the CCND1 allele in the cytoplasm, nucleolin transcription factor‐rich areas in the perinucleolar area, and truncated mRNA of cyclin D1, which is associated with poor prognosis. In a subset of patients who are cyclin D1 negative, cyclin D2/cyclin D3 translocations are observed and are associated with SOX‐11 positivity and a similar genomic profile and clinical course to that of cyclin D1‐positive MCL. SOX‐11 overexpression —Overexpression of SOX‐11 is observed in a majority of MCL patients .…”

Molecular crosstalk between cancer and neurodegenerative diseases

“…It exerts oncogenic functions through properties such as hyperactivation of CDK2 due to more stable LMW cyclin E/CDK2 complex formation [169], the resistance of LMW cyclin E/CDK2 complex to inhibitors p21 and p27 [170], altered substrate interactions [171], and cytoplasmic novel interactions that differ from the full-length cyclin E [172]. Like cytoplasmic LMW cyclin E, excessive cytoplasmic cyclin D1 also exerts oncogenic functions by promoting tumor cell invasion and metastasis [173][174][175] through cytoplasmic interactions [175,176].…”