LKB1, CCL2, and Macrophages: A New Axis of Endometrial Cancer Progression

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dc.contributor.advisorBrekken, Rolf A.en
dc.contributor.committeeMemberLum, Lawrenceen
dc.contributor.committeeMemberAmatruda, James F.en
dc.contributor.committeeMemberCastrillon, Diego H.en
dc.creatorPeña, Christopher Georgeen
dc.creator.orcid0000-0002-8121-8903
dc.date.accessioned2017-06-02T15:28:06Z
dc.date.available2017-06-02T15:28:06Z
dc.date.created2015-05
dc.date.issued2015-04-07
dc.date.submittedMay 2015
dc.date.updated2017-06-02T15:15:00Z
dc.description.abstractCancer of the uterus is a common malignancy in women with no adequate treatments for tumors that have progressed beyond the uterus. The serine-threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer. Combined genetic, proteomic, and in vivo studies in genetically engineered mouse models show that loss of LKB1 protein is associated with high grade, high stage tumors with unfavorable clinical outcomes. However, the mechanism(s) by which LKB1 drives malignant transformation of uterine cancers remains unclear. Here I show that LKB1 unexpectedly suppresses tumor progression via pAMPK dependent secretion of the inflammatory cytokine CCL2. Lkb1 inactivation in vivo resulted in abnormal production of CCL2, which led to recruitment of pro-tumorigenic macrophages (aka immunosuppressive macrophages) responsible for tumor invasion. Conditional inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression, increased survival, and significantly reduced infiltration of macrophages in the tumor microenvironment. In human primary endometrial cancers (EMCAs), loss of LKB1 protein was strongly associated with increased CCL2 and macrophage density. Additionally, high stage and high grade EMCAs were characterized by loss of LKB1 protein, elevated production of CCL2, and increased macrophage density. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating new therapeutic opportunities for targeting CCL2 and the tumor microenvironment.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc988778285
dc.identifier.urihttps://hdl.handle.net/2152.5/4126
dc.language.isoenen
dc.subjectAdenocarcinomaen
dc.subjectChemokine CCL2en
dc.subjectEndometrial Neoplasmsen
dc.subjectMacrophagesen
dc.subjectNeoplasm Proteinsen
dc.subjectProtein-Serine-Threonine Kinasesen
dc.titleLKB1, CCL2, and Macrophages: A New Axis of Endometrial Cancer Progressionen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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