title: Aberrant Activation of the RANK Signaling Receptor Induces Murine Salivary Gland Tumors.
abstract: Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis and treatment of aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management of malignant salivary gland cancers is undercut by our limited knowledge concerning the key molecular signals that underpin the etiopathogenesis of this rare and heterogeneous head and neck cancer. Without knowledge of the critical signals that drive salivary gland tumorigenesis, tumor vulnerabilities cannot be exploited that allow for targeted molecular therapies. This knowledge insufficiency is further exacerbated by a paucity of preclinical mouse models (as compared to other cancer fields) with which to both study salivary gland pathobiology and test novel intervention strategies. Using a mouse transgenic approach, we demonstrate that deregulation of the Receptor Activator of NFkB Ligand (RANKL)/RANK signaling axis results in rapid tumor development in all three major salivary glands. In line with its established role in other exocrine gland cancers (i.e., breast cancer), the RANKL/RANK signaling axis elicits an aggressive salivary gland tumor phenotype both at the histologic and molecular level. Despite the ability of this cytokine signaling axis to drive advanced stage disease within a short latency period, early blockade of RANKL/RANK signaling markedly attenuates the development of malignant salivary gland neoplasms. Together, our findings have uncovered a tumorigenic role for RANKL/RANK in the salivary gland and suggest that targeting this pathway may represent a novel therapeutic intervention approach in the prevention and/or treatment of this understudied head and neck cancer.
authors.affiliation: Department of Molecular Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, United States of America.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Szwarc
authors.affiliation: Department of Molecular Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, United States of America.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kommagani
authors.affiliation: Therapeutic Innovation Unit (TIU), Amgen Inc, Seattle, Washington, United States of America.
authors.forename: Allison P
authors.initials: AP
authors.lastname: Jacob
authors.affiliation: Therapeutic Innovation Unit (TIU), Amgen Inc, Seattle, Washington, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, and Michael E. DeBakey VAMC, Houston, Texas, United States of America.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Department of Molecular Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D049109:Cell Proliferation; D051379:Mice; D008822:Mice, Transgenic; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D012468:Salivary Gland Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse