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

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.

Collagen Family as Promising Biomarkers and Therapeutic Targets in Cancer

“…Particularly, the organization, distribution, and abundance of the “core matrisome” are important in malignant transformation and also in tumor progression and metastasis [ 43 ]. For example, COL12, secreted by cancer-associated fibroblasts (CAFs), alters COL1 organization and creates a pro-invasive microenvironment that supports metastatic dissemination ( Figure 1 ) [ 44 ]. CAFs originate from fibroblasts and mesenchymal stem cells, and they are the central players, and the functional regulators, present in the tumor mesenchyme which usually includes fibroblasts, immune cells, blood vessels, and the extracellular matrix [ 45 , 46 ].…”

“…Different studies showed that collagens are regulated by the TGF-β signaling pathway that regulates the ECM, mediates the EMT [ 98 , 99 ], and are implicated in PI3K/AKT pathway activation [ 32 , 94 ]. Papanicolaou et al evaluated the functional role of COL12, secreted by cancer-associated fibroblasts (CAFs), in primary breast tumor and metastasis formation and determined that COL12 is implicated in the spatial organization of COL1 fibrils in tumors, generating pro-invasive microenvironments [ 44 ].…”

“…In addition to the in vitro studies, there are also some in vivo studies conducted on animal models that underline the role of collagens in promoting tumor growth and creating a permissive tumor microenvironment for metastatic dissemination ( Table 2 ). This is due to a secretion of thinner collagen fibrils and/or by altering fibril organization, modifying tumor stiffness, and inducing a pro-invasive microenvironment in tumors [ 44 ] or by the modulation of the immune microenvironment [ 70 ].…”

Myeloid mechano-metabolic programming restricts anti-tumor immunity

“…The stiffened, fibrotic ECM in turn recruits TAMs 6,64 , promotes tumor aggression 65 , and metabolically reprograms tumor cells 40 and infiltrating immune cells. Our results demonstrate that the infiltrating TAMs themselves synthesize and secrete ECM proteins, including collagen VI and XII which can exert pleiotropic effects on the organization and stiffness of the tumor epithelium and noncellular and cellular stroma 66,67 . Thus, while cancer-associated fibroblasts are the primary source of fibrillar collagen in the TME, TAMs contribute specific collagens to the TME, such as the beaded filament collagen VI which forms microfibrillar networks that entrain epithelial basement membranes to interstitial ECM and facilitate wound healing, scar tissue formation, reepithelialization, and metastatic progression 68,69 .…”

Spatial analysis of the metastatic brain tumor immune and extracellular matrix microenvironment

“…Picrosirius red staining was performed, as previously described [25]. Tumor tissue slides were stained with Picrosirius red solution for 60 minutes.…”