Abstract
Introduction: Metastasis occurs when cancer cells form secondary tumors in distant areas of the body. Localization of RNAs in lamellipodial regions has been proposed to play an important role during metastatic progression. In one pathway, the tumor suppressor protein, adenomatous polyposis coli (APC) targets RNAs to cell protrusions. APC -associated mRNAs have been implicated in cellular migration and metastatic progression. Therefore, localization or not of these mRNAs has functional significance in cellular migration and metastasis. Additionally, It has been shown that cancer cells modulate their gene expression in response to the mechanical properties of the substrate. Furthermore, mRNA localization at adhesion sites is influenced by mechanical tension, which is adjusted by cells as a function of the mechanical properties of the cell environment. Therefore, mechanical properties of tissues may play a role during metastasis by modulating localization of mRNAs. As a result, this study investigates APC- associated mRNA localization as a function of substrate stiffness. Methods: We used the MCF10A cell series, a breast cancer progression model composed of cell lines representing pre-malignant to invasive transformation to investigate mRNA localization. By using in situ hybridization to fluorescently label mRNAs, and micropatterned polyacrylamide gels of varying stiffness, we observed APC associated mRNA localization. Glu-tubulin and vinculin were immunostained to study their relationship to mRNA localization. Results: On stiffer substrates (280kPa), we observed increased mRNA localization compared to softer substrates (0.87kPa). Staining of cytoskeletal elements such as Glu-tubulin and vinculin showed a correlation between the abundance and location of the proteins and APC-associated mRNAs. These results reveal biophysical roles of adhesion and cytoskeletal tension in regulating mRNAs to protrusions.
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