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Nat Cell Biol. 2014 Sep;16(9):889-901. doi: 10.1038/ncb3021. Epub 2014 Aug 24.

Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.

Author information

1
Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Canada.
2
Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, M5G 1X5, Canada.
3
Institute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, Germany.
4
Keio University, School of Medicine, Tokyo 160-8582, Japan.

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.

PMID:
25150980
DOI:
10.1038/ncb3021
[Indexed for MEDLINE]

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