# Matrix Metalloproteinase‐13 Is an Unfavorable Prognostic Factor in Chordoma by Digesting Growth Inhibitory Collagens

## TL;DR

This study shows that high levels of MMP13 in chordoma tumors are linked to worse outcomes, as it breaks down growth-inhibiting collagen, potentially making the cancer more aggressive.

## Contribution

The novel finding is that MMP13 degrades COL2 in chordoma, linking it to poor prognosis and suggesting it as a therapeutic target.

## Key findings

- Safranin-O-negative chordomas have shorter progression-free survival compared to safranin-O-positive ones.
- MMP13 expression is higher in safranin-O-negative chordomas and correlates with worse survival.
- MMP13 inhibition reduces collagen digestion and COL2 suppresses chordoma cell growth more than COL1.

## Abstract

Chordomas are low‐grade but invasive tumors with limited therapies. Some conventional chordomas exhibit cartilage‐like extracellular matrix (ECM). This study examined the expression and clinical significance of collagenases in chordomas.

Brachyury‐positive primary chordoma tissues were analyzed by immunohistochemistry for matrix metalloproteinase (MMP)13, MMP9, and cathepsin K, and by immunofluorescence for MMP13 and MMP9. ECM phenotype was categorized using safranin‐O staining, where safranin‐O marks cartilage‐like ECM. We compared MMP13 expression scores and progression‐free survival (PFS) between safranin‐O‐negative and ‐positive groups. Collagenase gene expression and protein localization in JHC7 cells were analyzed by quantitative PCR and immunocytochemistry, respectively. Collagen digestion activity was evaluated using fluorescein isothiocyanate–labeled type II collagen (COL2) in the presence or absence of an MMP13‐specific inhibitor. Cell growth was evaluated in the presence of type I collagen (COL1) or COL2.

Safranin‐O negative chordomas had shorter PFS than safranin‐O positive chordomas (p = 0.016). MMP13 was expressed in human chordoma tissues and JHC7 cells; the MMP13 expression score was higher in safranin‐O‐negative chordomas than in safranin‐O‐positive chordomas (p = 0.018). JHC7 cells digested COL2, and digestion was partially but significantly inhibited by an MMP13‐specific inhibitor (p < 0.05). COL2 inhibited the growth of JHC7 cells more strongly than COL1 in a dose‐dependent manner (p < 0.01).

MMP13 may promote aggressive behavior in chordoma by degrading growth‐inhibitory COL2‐rich ECM. These data support MMP13 as a potential unfavorable prognostic marker and therapeutic target in chordoma.