Glycation-mediated tissue-level remodeling of brain meningeal membrane by aging
H. M. Kim, S. Kim, J. Sim, B. S. Ma, I. Yong, Y. Jo, T.-S. Kim, J.-B. Chang, S.-H. Park, Y. Jeong* and P. Kim*
Aging Cell (2023)
We uncover glycation-mediated structural and functional changes in the collagen-enriched meningeal membrane of the human and mouse brain. Using an in vitro culture platform mimicking the meningeal membrane composed of fibrillar collagen, we showed that the accumulation of advanced glycation end products (AGEs) in the collagen membrane is responsible for glycation-mediated matrix remodeling. These changes influence fibroblast-matrix interactions, inducing cell-mediated ECM remodeling. These results suggest that glycation modification by meningeal fibroblasts is intimately linked to aging-related structural and functional alterations in the meningeal membrane.
Assessing Spatial Distribution of Multicellular Self-Assembly
Enables the Prediction of Phenotypic Heterogeneity in Glioblastoma
J. Cha, W. Sim, I. Yong, J. Park, J.-K. Shim, J. H. Chang, S.-G. Kang*, and P. Kim*
We propose the self-assembly-based evaluation method, which is capable of predicting inter/intracellular heterogeneity in glioblastoma. Depending on their self-assembly pattern, heterotypic multicellular aggregates (hMA) are formed by mixed populations of glioblastoma cells. The cells located at the outermost hMA exhibit a diminished temozolomide response, and are related with poor patient survival. Our ﬁndings imply that the multicellular self-assembly pattern is indicative of the intertumoral and intra-patient heterogeneity of glioblastomas, and is also prognostic of the therapeutic response.
Targeting Extracellular Matrix Glycation to Attenuate Fibroblast Activation
M. Jang, S. W. Oh, Y. Lee; J. Y. Kim, E. S. Ji, P Kim*
We demonstrate that AGEs accumulated in the ECM alter the fibroblast phenotype within a three-dimensional collagen matrix. Our results suggest that indirect/direct targeting of accumulated AGEs in the ECM has potential for targeting the tumor stroma to improve cancer therapy.
Cancer Cell-Sticky Hydrogels to Target the Cell Membrane of Invading Glioblastomas
J. Cha, P. Kim*
ACS Applied Materials & Interfaces(2021)
We design a cancer cell-sticky hydrogel (CSH) that interacts with the glioblastoma cells to impede their invasive motility by modifying the cell membrane with active thiol-enriched interfaces. Highly reactive thiols at the cell surface can make the infiltrated cancer cells adhere to the hydrogel, resulting in increased cell adhesion and decreased motility. Cotreatment with the CSH and chemical inhibitors of the major proinvasive molecules, focal adhesion kinase and hyaluronic acid synthase, maximized the invasion-inhibitory effect. In addition, a significant decrease in tumor mass was achieved via CSH implantation in mouse models.
Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer
M. Jang, J. An, S. W. Oh, J. Y. Lim, J. Kim, J. K. Choi*, J.-H. Cheong*, P. Kim*
Nature Biomedical Engineering(2021)
We show that in gastric cancer cells, the stiffness of the extracellular matrix reversibly regulates the DNA methylation of the promoter region of the mechanosensitive Yes-associated protein (YAP). Reciprocal interactions between YAP and the DNA methylation inhibitors GRHL2, TET2, and KMT2A can cause hypomethylation of the YAP promoter and stiffness-induced oncogenic activation of YAP. Direct alteration of extracellular cues via in situ matrix softening reversed YAP activity and the epigenetic program.