title: Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis.
abstract: Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis.
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Batista
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Maniati
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Tavora
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Delphine M
authors.initials: DM
authors.lastname: Lees
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fernandez
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: George
authors.initials: G
authors.lastname: Elia
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.affiliation: Department of Life Sciences, Sir Alexander Fleming building, Imperial College, London SW72AZ, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lo Celso
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hagemann
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodivala-Dilke
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency* / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006413:Hematopoietic System / Q000201:enzymology*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D019718:Receptors, CXCR4; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse