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Metabolic dependency of non-small cell lung cancer cells affected by three-dimensional scaffold and its stiffness

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Abstract

Three-dimensional (3D) extracellular matrix (ECM) microenvironment is an important regulator of the stiffness of the tumors. Cancer cells require heterogeneous metabolic phenotypes to cope with resistance in the malignant process. However, how the stiffness of the matrix affects the metabolic phenotypes of cancer cells, is lacking. In this study, the young’s modulus of the synthesized collagen-chitosan scaffolds was adjusted according to the percentage ratio of collagen to chitosan. We cultured non-small cell lung cancer (NSCLC) cells in four different microenvironments (two-dimensional (2D) plates, stiffest 0.5–0.5 porous collagen-chitosan scaffolds, middle stiff 0.5–1 porous collagen-chitosan scaffolds, and softest 0.5–2 porous collagen-chitosan scaffolds) to investigate the influence of the difference of 2D and 3D cultures as well as the 3D scaffolds with different stiffnesses on the metabolic dependency of NSCLC cells. The results revealed that NSCLC cells cultured in 3D collagen-chitosan scaffolds displayed higher capacity of mitochondrial metabolism and fatty acid metabolism than that cultured in 2D culture. The metabolic response of NSCLC cells is differential for 3D scaffolds with different stiffnesses. The cells cultured in middle stiff 0.5–1 scaffolds displayed a higher potential of mitochondrial metabolism than that of stiffer 0.5–0.5 scaffolds and softer 0.5–2 scaffolds. Furthermore, NSCLC cells culture in 3D scaffolds displayed drug resistance compared with that in 2D culture which maybe via the hyperactivation of the mTOR pathway. Moreover, the cells cultured in 0.5–1 scaffolds showed higher ROS levels, which were counterbalanced by an equally high expression of antioxidant enzymes when compared to the cells grown in 2D culture, which may be regulated by the increased expression of PGC-1α. Together, these results demonstrate that differences in the microenvironments of cancer cells profoundly impact their metabolic dependencies.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

Xiaorong Fu acknowledges support from the China Scholarship Council (grant number 201906050131).

Funding

This work was supported by the Japan Society for the Promotion of Science under the Grants-in-Aid for Scientific Research (S) (No. 17H06146).

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Authors and Affiliations

  1. Department of Micro-Nano Mechanical Science and Engineering, Graduate School of Engineering, Nagoya University, Nagoya City, Aichi State, Japan

    Xiaorong Fu, Yasuhiro Kimura, Yuhki Toku & Yang Ju

  2. College of Bioengineering, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing, 400030, People’s Republic of China

    Guanbin Song

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  1. Xiaorong Fu
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  2. Yasuhiro Kimura
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Contributions

X. F.: Investigation, Methodology, Visualization, Writing-original draft, Writing- review, and editing. Y. K.: Resources, Investigation, Methodology, Writing–Review, and Editing. Y. T.: Resources, writing–review, and editing. G. S.: Resources, writing review, and editing. Y. J.: Conceptualization, supervision, writing–original draft, writing–review & editing, funding acquisition. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Yang Ju.

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Key Points

• The microenvironment of 3D collagen-chitosan scaffolds reprograms the metabolic requirement of NSCLC cells.

• NSCLC cells cultured in 3D collagen-chitosan scaffolds revealed higher capacity of mitochondrial metabolism and fatty acid metabolism than that cultured in 2D plate.

• Metabolic dependency of NSCLC cells responded to the change of stiffness of 3D scaffolds

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Fu, X., Kimura, Y., Toku, Y. et al. Metabolic dependency of non-small cell lung cancer cells affected by three-dimensional scaffold and its stiffness. J Physiol Biochem 79, 597–611 (2023). https://doi.org/10.1007/s13105-023-00960-6

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  • DOI: https://doi.org/10.1007/s13105-023-00960-6

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