|The roles of cell stiffness in tumor cell tumorigenicity and nanoparticle-based mechanotargeting of soft cancer stem cell
|Tan, Youhua (BME)
Yang, Mo (BME)
Cells -- Mechanical properties
Cancer -- Research
Hong Kong Polytechnic University -- Dissertations
|Department of Biomedical Engineering
|186 pages : color illustrations
|Cancer has become one of the leading causes to human death globally. Except genetic and biochemical factors, mechanical forces exert important roles in tumorigenicity and metastasis, including tumor cell mechanics. Pre-clinical and clinical findings have demonstrated that highly malignant tumor cells or cancer stem cells (CSCs) exhibit lower cellular stiffness than non-CSCs, which are softer than their healthy counterparts, suggesting that there exists the correlation between cell mechanics and malignancy. However, it remains unclear whether and how cell mechanics regulate tumor cell tumorigenicity. Furthermore, whether cell mechanics can be harnessed for mechanotargeting of soft malignant CSCs remains unknown. To address the above fundamental questions, this project modulated cellular stiffness by targeting actomyosin contractility. Our results demonstrated that CSCs selected from hepatocarcinoma cells exhibited much lower stiffness than control cells, confirming the correlation between cell stiffness and stemness. Softening/stiffening tumor cells by targeting RhoA-ROCK-Myosin II signaling or F-actin significantly promoted/suppressed the colony formation and growth in soft fibrin and agar, the fraction of EpCAM+ and CD133+ subpopulation as well as the expressions of stemness genes in vitro, which could be rescued by stiffening/softening the cells concurrently. In addition, softening/stiffening cells facilitated/inhibited the tumor formation and growth in both subcutaneous and orthotropic tumor models. These results indicated that cell mechanics regulated tumor cell stemness and malignancy. Mechanistically, softening/stiffening decreased/increased APC expression, which then promoted/suppressed the nuclear translocation of β-catenin. The nuclear β-catenin might bound to the promoter of stemness gene Oct4 and influenced its transcription, which was essential in the self-renewal and tumorigenicity of tumor cells. As a result, cell mechanics regulated tumor cell malignancy through APC-β-catenin -Oct4 signaling.
Furthermore, we explored whether cell mechanics could be exploited in nanoparticle-based therapeutics for specific targeting of soft CSCs. We showed that tumor cells were softer but took up more graphene quantum dots (GQDs) in comparison with healthy cells. CSCs exhibited even lower stiffness but considerably higher cellular uptake than bulk tumor cells. Softening/stiffening cells enhanced/suppressed nanoparticle uptake and clathrin- and caveolae-mediated endocytosis, inhibition of which blocked the effect of cell softening on GQD uptake, indicating that cell mechanics regulated cellular uptake through endocytosis. Besides, soft CSCs exhibited enhanced drug release and cellular retention of Doxorubicin conjugated GQDs than stiff bulk tumor cells possibly due to the reduced intracellular pH and the regulation of exocytosis. Obviously, GQD-delivered Doxorubicin specifically eliminated CSCs both in vitro and in vivo and suppressed tumor growth without any obvious effect on animal body weight, while free drugs enriched the CSC fraction and reduced the body weight. Therefore, these findings demonstrated that cell mechanics regulated cellular uptake, drug release, and retention of drug-loaded nanoparticles for specific targeting of soft CSCs through the modulation of endocytosis, intracellular pH, and exocytosis. This study presented a new mechanism by which cell mechanics could be exploited in nanoparticle-based mechanomedicine for specific elimination of soft CSCs in effective cancer therapy.
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