3B kültür modelinden içgörüler: Doku sertliği ve matris bileşiminin tümör ilerlemesi üzerindeki sinerjistik etkisini keşfetmek

Extracellular Matrix (ECM) is a highly versatile network that regulates essential cellular processes. The matrix contains a wide array of proteins and carbohydrates, the composition and organization of which determines the mechanical and chemical signature of the ECM. The architecture of the ECM is tightly modulated in physiological events, whereas the chemical and mechanical properties are altered aberrantly during malignancy. The elevated stiffening of lung tissues due to excessive production of the matrix components, increased crosslinking, as well as the deregulation of enzymes involved in matrix remodeling and degradation accompany tumor progression. The aberrant increase in stiffness of tumor tissues is received through mechano sensitive receptors whose activation is required for the transmission of mechanical inputs into biochemical signals. As tumor tissues stiffen, elevated activation of surface receptors leads to epithelial to mesenchymal transition of cancer cells as well as promotes their stem cell like characteristics. Recapitulating the biochemical and biomechanical properties of the tumor microenvironment is of utmost importance in modelling cancer progression and enhancing the efficacy of therapeutic regimes. Hence, generating an in vitro model which enables alteration of tissue stiffening independently from ligand composition and concentration is of great value for examining the sole impact of stiffening on tumor progression. In addition, mimicking in vivo characteristics of tumor cells with respect to organ-specific cues in a 3D model where tissue stiffness is decoupled from other parameters enables comprehensive disease modeling. The impact of elevating tissue stiffness on modulating the malignancy of cancer cells in different ECM compositions has not been studied in an in vitro 3D culture model. In this study, a fully defined double network of alginate and two different matrices, decellularized healthy bovine lung ECM and tumorigenic basement membrane, is generated. Utilizing this model, it has been revealed that EMT activation and stemness abilities of cancer cells are promoted through synergic interactions between the stiffness of the microenvironment and tumorigenic composition of the matrix. In addition, the absence of PI3K gene, a well-known mediator of mechanotransduction process, is compensated through elevated stiffness of the tumor microenvironment.