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

Nat Commun. 2022 Aug 6;13(1):4587. doi: 10.1038/s41467-022-32255-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms* / pathology
  • Collagen
  • Collagen Type I
  • Collagen Type XII / metabolism*
  • Extracellular Matrix / pathology
  • Female
  • Humans
  • Neoplasm Metastasis* / pathology
  • Neoplasm Recurrence, Local / pathology
  • Proteomics
  • Tumor Microenvironment*


  • COL12A1 protein, human
  • Collagen Type I
  • Collagen Type XII
  • Collagen