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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Shimoda M,Principe S,Jackson HW,Luga V,Fang H,Molyneux SD,Shao YW,Aiken A,Waterhouse PD,Karamboulas C,Hess FM,Ohtsuka T,Okada Y,Ailles L,Ludwig A,Wrana JL,Kislinger T,Khokha Rdoi
10.1038/ncb3021subject
Has Abstractpub_date
2014-09-01 00:00:00pages
889-901issue
9eissn
1465-7392issn
1476-4679pii
ncb3021journal_volume
16pub_type
杂志文章abstract：:In three-dimensional matrices cancer cells move with a rounded, amoeboid morphology that is controlled by ROCK-dependent contraction of acto-myosin. In this study, we show that PDK1 is required for phosphorylation of myosin light chain and cell motility, both on deformable gels and in vivo. Depletion of PDK1 alters th...
journal_title：Nature cell biology
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pub_type： 杂志文章
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journal_title：Nature cell biology
pub_type： 杂志文章
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journal_title：Nature cell biology
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更新日期：2004-05-01 00:00:00
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journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1625
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journal_title：Nature cell biology
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更新日期：2010-07-01 00:00:00
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journal_title：Nature cell biology
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更新日期：2006-01-01 00:00:00
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journal_title：Nature cell biology
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更新日期：2005-02-01 00:00:00
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更新日期：2011-04-01 00:00:00
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journal_title：Nature cell biology
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更新日期：2004-08-01 00:00:00
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pub_type： 评论,杂志文章
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abstract：: ...
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