title: LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment.
abstract: Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor-promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Peña
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakada
authors.forename: Hatice D
authors.initials: HD
authors.lastname: Saatcioglu
authors.forename: Gina M
authors.initials: GM
authors.lastname: Aloisio
authors.forename: Ileana
authors.initials: I
authors.lastname: Cuevas
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
authors.forename: Jayanthi S
authors.initials: JS
authors.lastname: Lea
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Amelio
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D000818:Animals; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic; D059016:Tumor Microenvironment
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D004002:Clodronic Acid; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases