Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis

Michael Papanicolaou(University of Technology Sydney), Amelia L. Parker(Garvan Institute of Medical Research), Michelle Yam(Garvan Institute of Medical Research), Elysse C. Filipe(Garvan Institute of Medical Research), Sunny Z. Wu(Garvan Institute of Medical Research), Jessica L. Chitty(Garvan Institute of Medical Research), Kaitlin Wyllie(Garvan Institute of Medical Research), Emmi Tran(Garvan Institute of Medical Research), Ellie T. Y. Mok(Garvan Institute of Medical Research), Audrey Nadalini(Garvan Institute of Medical Research), Joanna N. Skhinas(Garvan Institute of Medical Research), Morghan C. Lucas(Garvan Institute of Medical Research), David Herrmann(Garvan Institute of Medical Research), Max Nobis(Garvan Institute of Medical Research), Brooke Pereira(Garvan Institute of Medical Research), Andrew M. K. Law(Garvan Institute of Medical Research), Lesley Castillo(Garvan Institute of Medical Research), Kendelle J. Murphy(Garvan Institute of Medical Research), Anaiis Zaratzian(Garvan Institute of Medical Research), Jordan F. Hastings(Garvan Institute of Medical Research), David R. Croucher(Garvan Institute of Medical Research), Elgene Lim(Garvan Institute of Medical Research), Brian G. Oliver(University of Technology Sydney), Fátima Valdés‐Mora(UNSW Sydney), Benjamin L. Parker(The University of Sydney), David Gallego‐Ortega(University of Technology Sydney), Alexander Swarbrick(Garvan Institute of Medical Research), Sandra O’Toole(Garvan Institute of Medical Research), Paul Timpson(Garvan Institute of Medical Research), Thomas R. Cox(Garvan Institute of Medical Research)
Nature Communications
August 6, 2022
10.1038/s41467-022-32255-7
Cited by 206Open Access
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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.

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