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Simultaneous targeting of CD44 and MMP9 catalytic and hemopexin domains as a therapeutic strategy
Gal Yosef1,2, Hezi Hayun1,2, Niv Papo1,2
1Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, PO Box 653, Beer-Sheva 84105, Israel.
Abstract:
Crosstalk of the oncogenic matrix metalloproteinase-9 (MMP9) and one of its ligands, CD44, involves cleavage of CD44 by the MMP9 catalytic domain, with the CD44-MMP9 interaction on the cell surface taking place through the MMP9 hemopexin domain (PEX). This interaction promotes cancer cell migration and invasiveness. In concert, MMP9-processed CD44 induces the expression of MMP9, which degrades ECM components and facilitates growth factor release and activation, cancer cell invasiveness, and metastasis. Since both MMP9 and CD44 contribute to cancer progression, we have developed a new strategy to fully block this neoplastic process by engineering a multi-specific inhibitor that simultaneously targets CD44 and both the catalytic and PEX domains of MMP9. Using a yeast surface display technology, we first obtained a high-affinity inhibitor for the MMP9 catalytic domain, which we termed C9, by modifying a natural non-specific MMP inhibitor, N-TIMP2. We then conjugated C9 via a flexible linker to PEX, thereby creating a multi-specific inhibitor (C9-PEX) that simultaneously targets the MMP9 catalytic and PEX domains and CD44. It is likely that, via its co-localization with CD44, C9-PEX may compete with MMP9 localization on the cell surface, thereby inhibiting MMP9 catalytic activity, reducing MMP9 cellular levels, interfering with MMP9 homodimerization, and reducing the activation of downstream MAPK/ERK pathway signaling. The developed platform could be extended to other oncogenic MMPs as well as to other important target proteins, thereby offering great promise for creating novel multi-specific therapeutics for cancer and other diseases.
Insights
Researchers developed a novel multi-specific inhibitor (C9-PEX) to block cancer progression by targeting both CD44 and matrix metalloproteinase-9 (MMP9). This innovative approach inhibits cancer cell migration and metastasis, offering new therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The oncogenic matrix metalloproteinase-9 (MMP9) and its ligand CD44 interact, promoting cancer cell migration and invasiveness.
- MMP9 cleaves CD44, and CD44 signaling further upregulates MMP9, creating a pro-cancer feedback loop.
- This MMP9-CD44 axis drives cancer progression, metastasis, and extracellular matrix degradation.
Purpose of the Study:
- To engineer a novel multi-specific inhibitor targeting both CD44 and MMP9 (catalytic and PEX domains).
- To develop a therapeutic strategy to simultaneously block the oncogenic MMP9-CD44 interaction and its downstream effects.
- To explore a new platform for developing multi-specific therapeutics for cancer.
Main Methods:
- Yeast surface display technology was employed to isolate a high-affinity inhibitor (C9) for the MMP9 catalytic domain.
- A natural MMP inhibitor, N-TIMP2, was modified to create C9.
- C9 was conjugated to the MMP9 hemopexin domain (PEX) to create the multi-specific inhibitor C9-PEX.
Main Results:
- The engineered multi-specific inhibitor C9-PEX simultaneously targets CD44 and both the catalytic and PEX domains of MMP9.
- C9-PEX is hypothesized to inhibit MMP9 activity by competing with MMP9 cell surface localization and reducing MMP9 levels.
- This inhibition is expected to reduce cancer cell invasiveness and downstream signaling pathways like MAPK/ERK.
Conclusions:
- A novel multi-specific inhibitor (C9-PEX) targeting the MMP9-CD44 axis was successfully developed.
- This inhibitor has the potential to block cancer progression, migration, and metastasis.
- The developed platform can be extended to target other oncogenic MMPs and proteins for novel therapeutic development.
