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Although clinical management of primary HPV(\u2009+\u2009) HNSCC is relatively successful, disease progression, including recurrence and metastasis, is often fatal. Moreover, patients with progressive disease face limited treatment options and significant treatment-associated morbidity. These clinical data highlight the need to identify targetable mechanisms that drive disease progression in HPV(\u2009+\u2009) HNSCC to prevent and\/or treat progressive disease. Interestingly, \u03b2-adrenergic signaling has recently been associated with pro-tumor processes in several disease types. Here we show that an aggressive murine model of recurrent\/metastatic HPV(\u2009+\u2009) HNSCC upregulates \u03b2<jats:sub>2<\/jats:sub>-adrenergic receptor (\u03b22AR) expression, concordant with significantly heightened mitochondrial metabolism, as compared with the parental model from which it spontaneously derived. \u03b2-Adrenergic blockade effectively inhibits in vitro proliferation and migratory capacity in this model, effects associated with an attenuation of hyperactive mitochondrial respiration. Importantly, propranolol, a clinically available nonselective \u03b2-blocker, significantly slows primary tumor growth, inhibits metastatic development, and shows additive benefit alongside standard-of-care modalities in vivo. Further, via CRISPR\/Cas9 technology, we show that the hyperactive mitochondrial metabolic profile and aggressive in vivo phenotype of this recurrent\/metastatic model are dependent on \u03b22AR expression. These data implicate \u03b22AR as a modulator of mitochondrial metabolism and disease progression in HPV(\u2009+\u2009) HNSCC, and warrant further investigation into the use of \u03b2-blockers as low cost, relatively tolerable, complementary treatment options in the clinical management of this disease.<\/jats:p>","DOI":"10.1038\/s41389-018-0090-2","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T09:15:35Z","timestamp":1538990135000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["\u03b22-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent\/metastatic HPV(+) HNSCC"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1669-0611","authenticated-orcid":false,"given":"Christopher T.","family":"Lucido","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan L.","family":"Callejas-Valera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0729-3964","authenticated-orcid":false,"given":"Paul L.","family":"Colbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1501-0418","authenticated-orcid":false,"given":"Daniel W.","family":"Vermeer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9950-7351","authenticated-orcid":false,"given":"W. 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