Breast cancer

Aussie research reveals collagen’s role in breast cancer metastasis

Collagen XII might have a role as a predictor of metastasis risk in patients with breast cancer including triple negative breast cancer, Australian researchers say.

Research from the Garvan Institute has highlighted the role of collagen XII in creating a “pro-invasive microenvironment supporting metastatic dissemination.”

The findings are consistent with other work showing that collagen XII is a marker of poor prognosis in colorectal cancer.

The latest Garvan research, published in Nature Communications, first demonstrated in a mouse model the temporal changes in the tumour extracellular matrix at early, mid and late stages of tumour development.

“Confirming previously published work, we note that the matrix glycoprotein osteopontin (SPP1) is highly abundant at the primary breast tumour site, a matrix element which has been shown to activate mammary fibroblasts into pro-tumourigenic cancer- associated fibroblasts (CAFs).”

The researchers confirmed that collagen XII is predominantly secreted by CAFs.

“Through cross-comparison of our proteomic profiling with single-cell transcriptomic analysis of tumours from matched animal models and patient tumours, we revealed the source of collagen XII as CAFs.”

They also demonstrated that collagen XII regulates collagen I fibril organisation – an increase in both collagen I bundle width and linearity as tumours progressed.

Collagen XII was also shown to be upregulated in human breast cancer samples from the Cancer Genome Atlas (TCGA) breast cancer cohort (BRCA).

“Kaplan–Meier analysis of collagen XII gene expression and patient survival in the same dataset demonstrated that high collagen XII expression in the primary tumour is significantly associated with both poor overall survival and poor progression-free survival.”

“The strong association of collagen XII expression with patient outcome, and in particular recurrence in early-stage patients, warrants further investigation to determine its potential as a biomarker of aggressive metastatic disease.”

They said their data suggests that “elevated collagen XII levels in the primary tumour facilitate cancer cells in disseminating to the secondary tissues such as the lung”.

“This increase in metastatic potential may arise from either more cancer cells disseminating from the primary tumour and/or an increased survival advantage that facilitates arrival at the lung.”

“In recent years, there has been a marked increase in interest in the role of the matrix in defining the properties of the tumour microenvironment, and our findings support the emerging hypothesis that future therapeutic approaches to ‘normalise’ or re-engineer the tumour stroma may offer the potential for significant translational impact in improving patient survival,” they concluded.

Therapeutic targets

The research was supervised by senior investigators Professor Paul Timpson and Associate Professor Thomas Cox.

Professor Timson, head of the invasion and metastasis lab at the Garvan, told the limbic that the tumour microenvironment was as fundamental in breast cancer as it was in pancreatic cancer.

He said while the paper focussed on collagen XII, it also highlighted many proteins and ECM glycoproteins as other potential therapeutic targets.

“Collagen XII is our poster child example. We’ve proven it’s associated with metastasis. That’s the biggest killer in breast cancer right now, right? I mean, no one dies of breast cancer; they only die of the mets. We need to understand the process to target it better in the future.”

He said the future has to include targeting the ecosystem surrounding the tumour.

“We need a more nuanced approach of looking at the environmental niche, then at the cancer with various chemos or immunotherapies. But at the same time, we are currently going after many of the other hits, collagen XII was just one of them to prove that this is a really good reservoir of new microenvironmental targets involved in structural components of breast cancer.”

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