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Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function.
Carter, Edward P; Yoneten, Kubra K; Gavara, Nuria; Tyler, Eleanor J; Gauthier, Valentine; Murray, Elizabeth R; Ten Dijke, Peter; Cameron, Angus J; Pearce, Oliver; Grose, Richard P.
Afiliação
  • Carter EP; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Yoneten KK; Department of Life Sciences, University of Bath, Bath, UK.
  • Gavara N; Centre for Therapeutic Innovation, Faculty of Science, University of Bath, Bath, UK.
  • Tyler EJ; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Gauthier V; Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain.
  • Murray ER; Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Ten Dijke P; Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Cameron AJ; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Pearce O; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.
  • Grose RP; Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
J Pathol ; 262(1): 90-104, 2024 01.
Article em En | MEDLINE | ID: mdl-37929635
ABSTRACT
Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor ß availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Miofibroblastos Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Miofibroblastos Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article