title: The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1.
abstract: The malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumor microenvironment that is composed of a variety of cell types, as well as noncellular components such as collagen. Although HRS cells harbor oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumor microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal center B cells, the presumed progenitors of HRS cells, upregulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently overexpress DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75 Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus, suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumor microenvironment in promoting the oncogenic effects of EBV.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; and.
authors.forename: Fathima Zumla
authors.initials: FZ
authors.lastname: Cader
authors.forename: Martina
authors.initials: M
authors.lastname: Vockerodt
authors.forename: Shikha
authors.initials: S
authors.lastname: Bose
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagy
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Brundler
authors.forename: Pamela
authors.initials: P
authors.lastname: Kearns
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000473:pathology; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D018858:Germinal Center / Q000166:cytology; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016539:Reed-Sternberg Cells / Q000166:cytology / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology; D014763:Viral Matrix Proteins / Q000235:genetics*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases