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

Michael Papanicolaou, Amelia L. Parker, Michelle Yam, Elysse C. Filipe, Sunny Z. Wu, Jessica L. Chitty, Kaitlin Wyllie, Emmi Tran, Ellie Mok, Audrey Nadalini, Joanna N. Skhinas, Morghan C. Lucas, David Herrmann, Max Nobis, Brooke A. Pereira, Andrew M. K. Law, Lesley Castillo, Kendelle J. Murphy, Anaiis Zaratzian, Jordan F. Hastings, David R. Croucher, Elgene Lim, Brian G. Oliver, Fatima Valdes Mora, Benjamin L. Parker, David Gallego-Ortega, Alexander Swarbrick, Sandra O’Toole, Paul Timpson () and Thomas R. Cox ()
Additional contact information
Michael Papanicolaou: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Amelia L. Parker: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Michelle Yam: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Elysse C. Filipe: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Sunny Z. Wu: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Jessica L. Chitty: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Kaitlin Wyllie: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Emmi Tran: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Ellie Mok: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Audrey Nadalini: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Joanna N. Skhinas: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Morghan C. Lucas: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
David Herrmann: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Max Nobis: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Brooke A. Pereira: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Andrew M. K. Law: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Lesley Castillo: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Kendelle J. Murphy: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Anaiis Zaratzian: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Jordan F. Hastings: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
David R. Croucher: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Elgene Lim: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Brian G. Oliver: University of Technology Sydney
Fatima Valdes Mora: Children’s Cancer Institute
Benjamin L. Parker: University of Sydney
David Gallego-Ortega: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Alexander Swarbrick: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Sandra O’Toole: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Paul Timpson: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre
Thomas R. Cox: The Garvan Institute of Medical Research and The Kinghorn Cancer Centre

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32255-7

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