title: Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness.
abstract: Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome.
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Avgustinova
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Marjan
authors.initials: M
authors.lastname: Iravani
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Fearns
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Pamela
authors.initials: P
authors.lastname: Klingbeil
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hanby
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Tumour Cell Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
authors.affiliation: Tumour Cell Biology Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|Tumour Microenvironment Team, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calvo
authors.affiliation: The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Isacke
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; C490508:Wnt7a protein, mouse