Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis
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2022-12-01
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Nature Communications
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NATURE PORTFOLIO
Melbourne Authors
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Anatomy and Neuroscience
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Journal Article
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Papanicolaou, M., Parker, A. L., Yam, M., Filipe, E. C., Wu, S. Z., Chitty, J. L., Wyllie, K., Tran, E., Mok, E., Nadalini, A., Skhinas, J. N., Lucas, M. C., Herrmann, D., Nobis, M., Pereira, B. A., Law, A. M. K., Castillo, L., Murphy, K. J., Zaratzian, A. ,... Cox, T. R. (2022). Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis. Nature Communications, 13 (1), https://doi.org/10.1038/s41467-022-32255-7.
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Abstract
The tumour stroma, and in particular the extracellular matrix (ECM), is a salient feature of solid tumours that plays a crucial role in shaping their progression. Many desmoplastic tumours including breast cancer involve the significant accumulation of type I collagen. However, recently it has become clear that the precise distribution and organisation of matrix molecules such as collagen I is equally as important in the tumour as their abundance. Cancer-associated fibroblasts (CAFs) coexist within breast cancer tissues and play both pro- and anti-tumourigenic roles through remodelling the ECM. Here, using temporal proteomic profiling of decellularized tumours, we interrogate the evolving matrisome during breast cancer progression. We identify 4 key matrisomal clusters, and pinpoint collagen type XII as a critical component that regulates collagen type I organisation. Through combining our proteomics with single-cell transcriptomics, and genetic manipulation models, we show how CAF-secreted collagen XII alters collagen I organisation to create a pro-invasive microenvironment supporting metastatic dissemination. Finally, we show in patient cohorts that collagen XII may represent an indicator of breast cancer patients at high risk of metastatic relapse.