{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/4126"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/4126","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"LKB1, CCL2, and Macrophages: A New Axis of Endometrial Cancer Progression","abstract":"Cancer 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.","abstract_html":"Cancer 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.","abstract_has_math":false,"creators":["Peña, Christopher George"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Brekken, Rolf A.","Lum, Lawrence","Amatruda, James F.","Castrillon, Diego H."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-06-02T15:28:06Z","date_published":"2017-06-02T15:28:06Z","updated_at":"2026-07-24T05:52:20Z","subjects":["Adenocarcinoma","Chemokine CCL2","Endometrial Neoplasms","Macrophages","Neoplasm Proteins","Protein-Serine-Threonine Kinases"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["988778285"],"render_values":[{"text":"988778285","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/4126","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Brekken, Rolf A.","Lum, Lawrence","Amatruda, James F.","Castrillon, Diego H."]},{"key":"dc:creator","label":"Author","values":["Peña, Christopher George"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2017-06-02T15:28:06Z","2015-05","2015-04-07","May 2015","2017-06-02T15:15:00Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Adenocarcinoma","Chemokine CCL2","Endometrial Neoplasms","Macrophages","Neoplasm Proteins","Protein-Serine-Threonine Kinases"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/4126","988778285"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Cancer 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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["LKB1, CCL2, and Macrophages: A New Axis of Endometrial Cancer Progression"]}]}],"canonical_facts":{"dc:contributor":["Brekken, Rolf A.","Lum, Lawrence","Amatruda, James F.","Castrillon, Diego H."],"dc:creator":["Peña, Christopher George"],"dc:date":["2017-06-02T15:28:06Z","2015-05","2015-04-07","May 2015","2017-06-02T15:15:00Z"],"dc:description":["Cancer 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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/4126","988778285"],"dc:language":["en"],"dc:subject":["Adenocarcinoma","Chemokine CCL2","Endometrial Neoplasms","Macrophages","Neoplasm Proteins","Protein-Serine-Threonine Kinases"],"dc:title":["LKB1, CCL2, and Macrophages: A New Axis of Endometrial Cancer Progression"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:20Z"}