title: Cdc42EP3/BORG2 and Septin Network Enables Mechano-transduction and the Emergence of Cancer-Associated Fibroblasts.
abstract: Cancer-associated fibroblasts (CAFs) are non-cancerous cells found in solid tumors that remodel the tumor matrix and promote cancer invasion and angiogenesis. Here, we demonstrate that Cdc42EP3/BORG2 is required for the matrix remodeling, invasion, angiogenesis, and tumor-growth-promoting abilities of CAFs. Cdc42EP3 functions by coordinating the actin and septin networks. Furthermore, depletion of SEPT2 has similar effects to those of loss of Cdc42EP3, indicating a role for the septin network in the tumor stroma. Cdc42EP3 is upregulated early in fibroblast activation and precedes the emergence of the highly contractile phenotype characteristic of CAFs. Depletion of Cdc42EP3 in normal fibroblasts prevents their activation by cancer cells. We propose that Cdc42EP3 sensitizes fibroblasts to further cues-in particular, those activating actomyosin contractility-and thereby enables the generation of the pathological activated fibroblast state.
authors.affiliation: Tumour Cell Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK; Tumour Microenvironment Team, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW2 6JB, UK. Electronic address: fernando.calvo@icr.ac.uk.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calvo
authors.affiliation: Tumour Microenvironment Team, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW2 6JB, UK.
authors.forename: Romana
authors.initials: R
authors.lastname: Ranftl
authors.affiliation: Tumour Cell Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Hooper
authors.affiliation: Tumour Microenvironment Team, Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW2 6JB, UK.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Farrugia
authors.affiliation: London Centre for Nanotechnology, University College London, London WC1H 0AH, UK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Emad
authors.initials: E
authors.lastname: Moeendarbary
authors.affiliation: Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bruckbauer
authors.affiliation: Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Facundo
authors.initials: F
authors.lastname: Batista
authors.affiliation: London Centre for Nanotechnology, University College London, London WC1H 0AH, UK; Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charras
authors.affiliation: Tumour Cell Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: erik.sahai@crick.ac.uk.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D020555:GTP-Binding Protein Regulators / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D058112:Septins / Q000378:metabolism*; D015854:Up-Regulation; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020555:GTP-Binding Protein Regulators; D058112:Septins; D020764:cdc42 GTP-Binding Protein