Page 216 - Haematologica March 2020

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Haematologica 2020 Volume 105(3):730-740
Non-Hodgkin Lymphoma
CDCA7 finely tunes cytoskeleton dynamics to promote lymphoma migration and invasion
Carla Martín-Cortázar,1 Yuri Chiodo,1 Raul Jiménez-P.,1 Manuel Bernabé,2 María Luisa Cayuela,2 Teresa Iglesias3,4 and Miguel R. Campanero1,5
1Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid; 2Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia; 3Department of Endocrine and Nervous Systems Pathophysiology, Instituto de Investigaciones Biomédicas Alberto Sols, Madrid ; 4Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid and 5Centro de Investigaciones Biomédicas en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
ABSTRACT
Metastases, the major cause of death from cancer, require cells’ acquisition of the ability to migrate and involve multiple steps, including local tumor cell invasion and basement membrane pen- etration. Certain lymphoid tumors are highly metastatic, but the mecha- nisms of invasion by lymphoma cells are poorly understood. We recently showed that CDCA7, a protein induced by MYC, is overexpressed in lym- phoid tumors and that its knockdown decreases lymphoid tumor growth without inhibiting the proliferation of normal cells. Here we show that CDCA7 is critical for invasion and migration of lymphoma cells. Indeed, CDCA7 knockdown in lymphoma cells limited tumor cell invasion in matrigel-coated transwell plates and tumor invasion of neighboring tissues in a mouse xenograft model and in a zebrafish model of cell invasion. CDCA7 silencing markedly inhibited lymphoma cell migration on fibronectin without modifying cell adhesion to this protein. Instead, CDCA7 knockdown markedly disrupted the precise dynamic reorganiza- tion of actomyosin and tubulin cytoskeletons required for efficient migra- tion. In particular, CDCA7 silencing impaired tubulin and actomyosin cytoskeleton polarization, increased filamentous actin formation, and induced myosin activation. Of note, inhibitors of actin polymerization, myosin II, or ROCK reestablished the migration capacity of CDCA7- silenced lymphoma cells. Given the critical role of CDCA7 in lymphoma- genesis and invasion, therapies aimed at inhibiting its expression or activity might provide significant control of lymphoma growth, invasion, and metastatic dissemination.
Introduction
Cancer cells acquire molecular alterations relative to their normal counterparts which confer them endless proliferative activity, resistance to death, and the capac- ity to metastasize, among other traits. Metastases are the major cause of death from cancer and their biological heterogeneity creates a critical obstacle to treat- ment.1 Certain lymphoid tumors are highly metastatic, invading the spleen, lymph nodes and central nervous system. Indeed, direct invasion of the central nervous system occurs in 5% of all patients with non-Hodgkin lymphoma.2 The incidence varies with clinical aggressiveness and can be as high as 27% for very aggressive lymphomas2 and as high as 70% in the case of acute lymphoblastic leukemia in the absence of central nervous system-directed prophylactic treatment.3
Metastases of epithelial cancers involve local tumor cell invasion, basement membrane penetration, intravasation into blood or lymphatic vessels followed by exit from the circulation, and colonization of distant tissues. Most carcinoma cells produce matrix-degrading enzymes to clear a path for tissue invasion. The matrix metalloproteinase (MMP) family, a diverse group of calcium-dependent zinc-con-
Correspondence:
MIGUEL R. CAMPANERO
mcampanero@iib.uam.es
Received: December 31, 2018. Accepted: June 19, 2019. Pre-published: June 20, 2019.
doi:10.3324/haematol.2018.215459
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/730
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