title: Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.
abstract: Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: Ruiz de Garibay
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Herranz
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Llorente
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Boni
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra-Musach
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mateo
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Aguilar
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Gómez-Baldó
authors.affiliation: Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Petit
authors.affiliation: Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: August
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Fina
authors.initials: F
authors.lastname: Climent
authors.affiliation: Department of Pathology, Vall d'Hebron Hospital, Barcelona, Catalonia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Álex
authors.initials: Á
authors.lastname: Cordero
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: González-Suárez
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: José Vicente
authors.initials: JV
authors.lastname: Sánchez-Mut
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Llatjós
authors.affiliation: Department of Pathology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Varela
authors.affiliation: Cruces University Hospital, BioCruces Research Institute, University of the Basque Country, Barakaldo, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: López
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: García
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Extremera
authors.affiliation: Department of Radiology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Gumà
authors.affiliation: Department of Radiology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Ortega
authors.affiliation: Department of Gynecology, University Hospital of Bellvitge, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Plà
authors.affiliation: Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Pernas
authors.affiliation: Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Catalina
authors.initials: C
authors.lastname: Falo
authors.affiliation: Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Morilla
authors.affiliation: Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Campos
authors.affiliation: Department of Medical Oncology, Breast Cancer Unit, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gil
authors.affiliation: Department of Pulmonology, Lung Transplant Unit, Lymphangioleiomyomatosis (LAM) Clinic, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Román
authors.affiliation: Department of Pneumology, University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain; Biomedical Research Centre Network for Respiratory Diseases (CIBERES), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Molina-Molina
authors.affiliation: Department of Pneumology, University Hospital Clínica Puerta del Hierro, Madrid, Spain.
authors.forename: Piedad
authors.initials: P
authors.lastname: Ussetti
authors.affiliation: Department of Pneumology, University Hospital Clínica Puerta del Hierro, Madrid, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Laporta
authors.affiliation: Department of Pneumology, Instituto de Investigación Sanitaria La Princesa, Hospital La Princesa, Madrid, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Valenzuela
authors.affiliation: Department of Pneumology, Instituto de Investigación Sanitaria La Princesa, Hospital La Princesa, Madrid, Spain.
authors.forename: Julio
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authors.lastname: Ancochea
authors.affiliation: Biomedical Research Centre Network for Respiratory Diseases (CIBERES), Madrid, Spain; Department of Pneumology, Hospital Clinic of Barcelona, Agusti Pi Suñer Biomedical Research Institute (IDIBAPS), Barcelona, Catalonia, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Xaubet
authors.affiliation: Department of Pneumology, Henares Hospital, Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Casanova
authors.affiliation: Program Against Cancer Therapeutic Resistance (ProCURE), Breast Cancer and Systems Biology, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
authors.forename: Miguel Angel
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mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000556:secondary; D018192:Lymphangioleiomyomatosis / Q000097:blood* / Q000473:pathology; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins