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Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.
- Source :
-
Nature cell biology [Nat Cell Biol] 2014 Sep; Vol. 16 (9), pp. 889-901. Date of Electronic Publication: 2014 Aug 24. - Publication Year :
- 2014
-
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.
- Subjects :
- ADAM Proteins metabolism
ADAM10 Protein
Amyloid Precursor Protein Secretases metabolism
Animals
Cell Line, Tumor
Cell Movement
Exosomes physiology
Female
Fibroblasts pathology
Humans
Lung Neoplasms enzymology
Mammary Neoplasms, Experimental enzymology
Membrane Proteins metabolism
Metalloendopeptidases metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplasm Transplantation
Phenotype
Signal Transduction
Tissue Inhibitor of Metalloproteinases deficiency
Tumor Burden
Fibroblasts metabolism
Lung Neoplasms secondary
Mammary Neoplasms, Experimental pathology
Tissue Inhibitor of Metalloproteinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4679
- Volume :
- 16
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Nature cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 25150980
- Full Text :
- https://doi.org/10.1038/ncb3021