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

Masayuki Shimoda, Simona Principe, Hartland W. Jackson, Valbona Luga, Hui Fang, Sam D. Molyneux, Yang W. Shao, Alison Aiken, Paul D. Waterhouse, Christina Karamboulas, Franz M. Hess, Takashi Ohtsuka, Yasunori Okada, Laurie Ailles, Andreas Ludwig, Jeffrey L. Wrana, Thomas Kislinger, Rama Khokha

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107 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)889-901
Number of pages13
JournalNature Cell Biology
Volume16
Issue number9
DOIs
Publication statusPublished - 2014 Sep

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Shimoda, M., Principe, S., Jackson, H. W., Luga, V., Fang, H., Molyneux, S. D., Shao, Y. W., Aiken, A., Waterhouse, P. D., Karamboulas, C., Hess, F. M., Ohtsuka, T., Okada, Y., Ailles, L., Ludwig, A., Wrana, J. L., Kislinger, T., & Khokha, R. (2014). Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nature Cell Biology, 16(9), 889-901. https://doi.org/10.1038/ncb3021