title: Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.
abstract: Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, Timps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Simona
authors.initials: S
authors.lastname: Principe
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Hartland W
authors.initials: HW
authors.lastname: Jackson
authors.affiliation: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, M5G 1X5, Canada.
authors.forename: Valbona
authors.initials: V
authors.lastname: Luga
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Yang W
authors.initials: YW
authors.lastname: Shao
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Alison
authors.initials: A
authors.lastname: Aiken
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Waterhouse
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Karamboulas
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Franz M
authors.initials: FM
authors.lastname: Hess
authors.affiliation: Keio University, School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohtsuka
authors.affiliation: Keio University, School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Ailles
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, M5G 1X5, Canada.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D055354:Exosomes / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D015398:Signal Transduction; D019714:Tissue Inhibitor of Metalloproteinases / Q000172:deficiency / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D008565:Membrane Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human