Targeting extracellular matrix glycation to attenuate fibroblast activation

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Tumor extracellular matrix (ECM) remodeling influences cancer progression.
• Non-enzymatic glycation forms advanced glycation end-products (AGEs), altering ECM properties.
• The impact of AGE-mediated ECM changes on stromal cells, particularly fibroblasts, is not fully understood.

Purpose of the Study:

• To investigate how AGEs in the ECM affect fibroblast phenotype.
• To elucidate the mechanisms linking AGEs, matrix stiffness, and fibroblast activation.
• To evaluate the therapeutic potential of targeting AGEs and their effects on the tumor microenvironment.

Main Methods:

• Utilized a three-dimensional collagen matrix model.
• Investigated AGE accumulation and its interaction with the receptor for AGEs (RAGE).
• Assessed integrin-mediated mechanotransduction and focal adhesion (FA) signaling.
• Employed neutralizing antibodies against RAGE and FA signaling inhibitors.
• Tested the AGE cross-link breaker phenyl-4,5-dimethylthiazolium bromide (ALT-711).

Main Results:

• AGEs in the ECM induced a cancer-associated fibroblast (CAF)-like phenotype in fibroblasts.
• Both AGE-RAGE interaction and integrin-mediated mechanotransduction were upregulated in glycated matrices.
• Blocking RAGE or FA signaling inhibited fibroblast activation.
• ALT-711 reduced CAF-like transformation by inhibiting AGE-RAGE interaction and decreasing matrix stiffness.
• Reduced matrix stiffness attenuated fibroblast activation.

Conclusions:

• AGE accumulation in the tumor ECM promotes fibroblast activation towards a CAF-like phenotype.
• Fibroblast activation is mediated by a combination of AGE-RAGE signaling and mechanotransduction.
• Targeting AGEs in the ECM, either directly or indirectly by reducing matrix stiffness, presents a promising strategy for cancer therapy.
• Extracellular-reversion strategies targeting non-enzymatic ECM glycation can regulate fibroblast activation in the tumor stroma.