Jang, Minjeong Oh, Seung Won Lee, Yunji Kim, Jin Young Ji, Eun Sun Kim, Pilnam 2024-01-19T12:31:09Z 2024-01-19T12:31:09Z 2022-07-14 2022-03 1742-7061 https://pubs.kist.re.kr/handle/201004/115510 The extracellular matrix (ECM) of the tumor microenvironment undergoes constant remodeling that alters its biochemical and mechano-physical properties. Non-enzymatic glycation can induce the formation of advanced glycation end-products (AGEs), which may cause abnormal ECM turnover with excessively cross-linked collagen fibers. However, the subsequent effects of AGE-mediated matrix remodeling on the characteristics of stromal cells in tumor microenvironments remain unclear. Here, we demonstrate that AGEs accumulated in the ECM alter the fibroblast phenotype within a three-dimensional collagen matrix. Both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction signaling were up-regulated in glycated collagen matrix, leading to fibroblast activation to acquire a cancer-associated fibroblast (CAF)-like phenotype. These effects were blocked with neutralizing antibodies against RAGE or the inhibition of focal adhesion (FA) signaling. An AGE cross-link breaker, phenyl-4,5dimethylthiazolium bromide (ALT 711), also reduced the transformation of fibroblasts into the CAF-like phenotype because of its dual inhibitory role in the AGE-modified matrix. Apart from targeting the AGE & ndash; RAGE interaction directly, the decreased matrix stiffness attenuated fibroblast activation by inhibiting the downstream cellular response to matrix stiffness. Our results suggest that indirect/direct targeting of accumulated AGEs in the ECM has potential for targeting the tumor stroma to improve cancer therapy. Statement of significance Advanced glycated end-products (AGEs)-modified extracellular matrix (ECM) is closely associated with pathological states and is recognized as a critical factor that precedes tumorigenesis. While increased matrix stiffness is known to induce fibroblast activation, less is known about how both biochemical and mechano-physical changes in AGE-mediated matrix-remodeling cooperate to produce a myofibroblastic cancer-associated fibroblast (CAF)-like phenotype. For the first time, we found that both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction were up-regulated in glycated collagen matrix, leading to fibroblast activation. We further demonstrated that an AGE cross-link breaker, ALT-711, reduced the CAF-like transformation because of its dual inhibitory role in the AGE-modified matrix. Our findings offer promising extracellular-reversion strategies targeting the non-enzymatic ECM glycation, to regulate fibroblast activation. (C) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. English Elsevier BV Targeting extracellular matrix glycation to attenuate fibroblast activation Article 10.1016/j.actbio.2022.01.040 1 Acta Biomaterialia, v.141, pp.255 - 263 Acta Biomaterialia 141 255 263 N scie scopus 000820110800001 2-s2.0-85123724937 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article END-PRODUCTS CANCER COLLAGEN MODEL BETA AGE Extracellular matrix (ECM) Advanced Glycation End-products (AGEs) Fibroblast activation ECM-targeting