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Abstract
Recent studies undoubtedly show that the mammalian target of rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are important mediators of mechanical cues. The crosstalk between these pathways as well as de-regulation of their signaling has been implicated in multiple tumor types, including liver tumors. Additionally, physical cues from 3D microenvironments have been identified to alter gene expression and differentiation of different cell lineages. However, it remains incompletely understood how physical constraints originated in 3D cultures affect cell plasticity and what the key mediators are of such process. In this work, we use collagen scaffolds as a model of a soft 3D microenvironment to alter cellular size and study the mechanotransduction that regulates that process. We show that the YAP-mTOR axis is a downstream effector of 3D cellular culture-driven mechanotransduction. Indeed, we found that cell mechanics, dictated by the physical constraints of 3D collagen scaffolds, profoundly affect cellular proliferation in a YAP–mTOR-mediated manner. Functionally, the YAP–mTOR connection is key to mediate cell plasticity in hepatic tumor cell lines. These findings expand the role of YAP–mTOR-driven mechanotransduction to the control hepatic tumor cellular responses under physical constraints in 3D cultures. We suggest a tentative mechanism, which coordinates signaling rewiring with cytoplasmic restructuring during cell growth in 3D microenvironments.
Highlights
Despite technical advances and numerous experimental evidence, the concept that the mechanical cues and properties of a culture environment play a crucial role in modulating cell behaviors only recently became widely accepted [1]
Summarizing the data until now, we revealed that culturing Alexander and HepG2 cells in collagen scaffolds leads to YAP and phosphorylated form of the mTOR (pmTOR) downregulation and cytosolic translocation, which is accompanied by activated autophagic flux
The present study demonstrated control of liver tumor cell plasticity by physical cues originated in a 3D microenvironment and identified the participation of the YAP–mammalian target of rapamycin (mTOR) axis in mechanically-driven regulation of cell proliferation
Summary
Despite technical advances and numerous experimental evidence, the concept that the mechanical cues and properties of a culture environment play a crucial role in modulating cell behaviors only recently became widely accepted [1]. Liver stiffness was shown to be associated with the development of fibrosis and liver cancer [6,7]. A recent study revealed that a soft ECM enhances the cancer stem cell phenotype of HCC cells [16]. Molecular foundations that mediate microenvironment stiffness-induced development of liver pathologies, tumor formation, are still not fully understood. The majority of current research is focused on signaling in HCC cells, which is biased by rather stiff ECM (i.e., stiffness about 10–30 kPa), whereas little attention is given to molecular mechanisms affected by soft ECM (i.e., stiffness lower than 1 kPa) [17,18,19]
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