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3D gelatin network properties affect the activation pattern of cancer-associated fibroblasts
Somayadineshraj D.,Minwoo Kang,Tae Yoon Kwon,Young Bin Cho,Jennifer H. Shin 대한기계학회 2021 대한기계학회 춘추학술대회 Vol.2021 No.4
Cancer-associated fibroblasts (CAFs) are among the most abundant and predominant cell types within the tumor microenvironment (TME). CAFs are originated from diverse cell populations through different mechanisms. CAF activation is considered a multi-step process, where enhanced ECM (Extracellular matrix) production facilitates desmoplasia under inflammation, promoting tumor growth and CAF activation in a feed-forward loop. However, the specific mechanism on how the ECM modulates CAF initiation remains elusive. Here we introduce a 3D in vitro model based on gelatin protein to mimic the tumor's paracrine interaction to investigate ECM density's impact in activating fibroblasts into CAF in MCF-7 conditioned media. Interestingly, we found a less dense (LD) network facilitated CAF activation than a highly dense (HD) network, accompanied by higher spreading and contractility of the cells. Given the larger spreading area of the cells shown in the LD network, we further investigated the Akt/mTOR pathway's role to suggest that the LD matrix promoted CAF activation by inducing higher tensional integrity in fibroblasts resulting in upregulation of Akt/mTOR signaling cascade. Based on these results, we propose a novel strategy for non-desmoplastic activation of CAFs by utilizing an electrospun gelatin-based in vitro 3D network of specific density and porosity.