title: STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment.
abstract: Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ's microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.|Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.
authors.forename: Lidia Santos
authors.initials: LS
authors.lastname: Silva
authors.affiliation: Instituto de Tecnologia Quimica e Biológica (ITQB) António Xavier, Universidade NOVA, Oeiras, Portugal.
authors.forename: Luis Gafeira
authors.initials: LG
authors.lastname: Goncalves
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.|Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Silva
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.|Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.
authors.forename: Germana
authors.initials: G
authors.lastname: Domingues
authors.affiliation: Medical Faculty, University of Porto, Porto, Portugal.|Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Valdemar
authors.initials: V
authors.lastname: Maximo
authors.affiliation: Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Instituto de Medicina Molecular da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Sergio
authors.initials: S
authors.lastname: Dias
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.|Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Felix
authors.affiliation: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal. jacinta.serpa@fcm.unl.pt.|Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal. jacinta.serpa@fcm.unl.pt.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Serpa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002584:Cervix Uteri / Q000473:pathology; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000096:biosynthesis / Q000235:genetics*; D000071316:Forkhead Box Protein O3 / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; C107585:FOXM1 protein, human; C499517:FOXO3 protein, human; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; C115081:MCTS1 protein, human; D015513:Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019344:Lactic Acid
keywords: MCT1; Metabolic symbiosis; New therapeutic target; STAT3-FOXM1; Uterine cervix cancer