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Cytoskeleton Remodeling as a Potential Regulator of Metabolic Rewiring in Liver Cancer Cells

Emerging evidence has revealed that physical stimuli from the cellular microenvironment play a crucial role in transmitting mechanical signals that regulate key cellular functions such as proliferation, migration, and malignant transformation [1-3]. It is now clear that tumor cells are subjected to a dynamic array of mechanical forces that can drive metabolic rewiring—a process that allows them to adapt to their changing environment [4, 5]. Physical abnormalities within tumors, including elevated solid stress, increased interstitial fluid pressure, and enhanced tissue stiffness, have all been linked to cancer progression and development [3]. These mechanical forces, transmitted through mechanotransduction pathways, can profoundly impact cellular metabolism. However, the mechanisms by which tumor cells adapt their metabolic processes in response to these external mechanical cues remain poorly understood.

One compelling hypothesis is that cytoskeletal remodeling—driven by these physical cues—plays a central role in facilitating tumorigenesis. The cytoskeleton, a dynamic network of protein filaments, not only supports cell shape and motility but also transmits mechanical signals that may reprogram cellular metabolism to support tumor growth and survival.

Our research group has demonstrated that individual cell remodeling in liver cancer can lead to large-scale reorganization of cell colonies, allowing them to adapt to lateral forces imposed by external constraints [6]. Notably, we found that liver cancer cells grown in a very soft microenvironment (with an average storage modulus, G’, of ~94 Pa) exhibit reduced cellular proliferation and altered cell size, primarily through a YAP-mTOR-mediated pathway [7]. This suggests that microenvironmental stiffness can significantly influence the behavior of hepatic tumor cells.

Despite these insights, the molecular mechanisms that link microenvironmental stiffness to the development of liver pathologies—particularly cancer—are still not fully understood.

To address this gap, our ongoing research utilizes advanced cell culture models designed to mimic changes in the tumor microenvironment’s stiffness. By investigating how cytoskeletal reorganization correlates with metabolic rewiring in liver cancer cells, we aim to uncover new insights into the mechanical and molecular drivers of liver cancer progression. This research may ultimately reveal novel therapeutic targets that could disrupt the mechanical-metabolic feedback loop contributing to tumorigenesis.

References

1.         Chaudhuri, O., et al., Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature, 2020. 584: p. 535-546.

2.         Sun, Y., C.S. Chen, and J. Fu, Forcing stem cells to behave: a biophysical perspective of the cellular microenvironment. Annu Rev Biophys, 2012. 41: p. 519-42.

3.         Nia, H.D.T., L.L. Munn, and R.K. Jain, Physical traits of cancer. Science, 2020. 370: p. eaaz0868.

4.         Park, J.S., et al., Mechanical regulation of glycolysis via cytoskeleton architecture. Nature, 2020. 578: p. 621-626.

5.         Lunova, M., et al., Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment. Biomaterials and Biosystems, 2024. 14: p. 100093.

6.         Frtus, A., et al., Mechanical regulation of mitochondrial dynamics and function in a 3D-engineered liver tumor microenvironment. ACS Biomaterials Science & Engineering, 2023. 9: p. 2408-2425.

7.         Frtus, A., et al., Hepatic tumor cell morphology plasticity under physical constraints in 3D cultures driven by YAP-mTOR axis. Pharmaceuticals (Basel), 2020. 13: p. 430.

Internship at the Laboratory of Biophysics: https://www.fzu.cz/en/research/divisions-and-departments/division-4/department-21/laboratory-2102