Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism

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dc.contributor.advisorBuszczak, Michaelen
dc.contributor.committeeMemberO'Donnell, Kathryn A.en
dc.contributor.committeeMemberMendell, Joshua T.en
dc.contributor.committeeMemberMorrison, Sean J.en
dc.creatorUpdegraff, Barrett Loganen
dc.creator.orcid0000-0002-9523-6280
dc.date.accessioned2019-01-03T21:15:53Z
dc.date.available2019-01-03T21:15:53Z
dc.date.created2018-12
dc.date.issued2018-11-26
dc.date.submittedDecember 2018
dc.date.updated2019-01-03T21:15:54Z
dc.description.abstractPathways underlying metabolic reprogramming in cancer remain incompletely understood. We identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes transformation of immortalized human bronchial epithelial cells. TMPRSS11B is upregulated in human lung squamous cell cancers and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B depletion in human lung squamous cell cancer reduced transformation and tumor growth. TMPRSS11B harbors an extracellular protease domain and we hypothesized that catalysis of a membrane bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that wild-type, but not catalytic mutants of TMPRSS11B promotes membrane release of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1 and MCT4. To investigate whether TMPRSS11B regulates lactate transport, we monitored intracellular lactate content and lactate secretion. Our data suggest TMPRSS11B regulates cellular lactate levels by interacting and co-localizing with Basigin and MCT4 at the plasma membrane to enhance their lactate export efficiency. Specifically, TMPRSS11B expression promoted lactate secretion concomitant with reduced levels of intracellular lactate content. Conversely, TMPRSS11B depletion in lung squamous cell cancer lines resulted in substantial accumulation of intracellular lactate. We detail a novel metabolic role of TMPRSS11B and this work identifies an oncogenic transmembrane protease that promotes tumorigenesis, thereby uncovering a new enzymatic activity that may be targeted for cancer therapy. Interrogation of lactate metabolism in vivo will ultimately guide these therapies and contribute to our growing knowledge of lactate biology.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1080644331
dc.identifier.urihttps://hdl.handle.net/2152.5/6153
dc.language.isoenen
dc.subjectCarcinoma, Non-Small-Cell Lungen
dc.subjectGlucoseen
dc.subjectLactic Aciden
dc.subjectMembrane Proteinsen
dc.subjectSerine Endopeptidasesen
dc.titleTransmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolismen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineGenetics and Developmenten
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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