Study Reveals Nanomechanical Signatures of Breast Cancer-Derived Small Extracellular Vesicles and their Correlation with Tumor Malignancy

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Small extracellular vesicles (sEVs) are now increasingly recognized as specific cellular messengers in influencing the recipient cells and facilitating intercellular communication. Together with their diffusion and transport in the extracellular matrix (ECM), sEVs play a significant role in regulating tumor microenvironment. The nanomechanical properties of the sEVs determine their behaviors in the cellular processes such as adhesion with cells, endocytosis, exocytosis, and uptaking by cells, ultimately affecting the modification effect on the target cell. In addition, the mechanical properties of sEVs will also affect the process of their traversing in the ECM, which is significant for the transmission of biological information to the distal metastases.

Studies have demonstrated that changes in the mechanical properties of cells in the process of malignant transformation cause changes in their behavior and tumor microenvironment, determining tumor invasion and metastasis. sEVs are endosome-derived membranous vesicles released by almost all the cells and are abundant in various body fluids. Since they carry the plasma membranes and the intracellular contents such as the cytoplasmic proteins and the nucleic acids from the source cells, their nanomechanical properties represent the ones of the source cells, and they therefore become the desired model to study the nanomechanical signatures of the tumor cells. The mechanical properties of sEVs are closely related to their behaviors in the fundamental processes such as cell-cell communication, diffusion and transport in the ECM and in the circulating systems, and ultimately decide tumor invasion and metastasis. Several recent studies estimated the stiffness of tumor-derived sEVs by measuring Young’s modulus that represented the stiffness of the sEVs taking the sEVs as an integral elastic spherical model. However, the contribution of the intrinsic mechanical properties that play essential functions in the mechanical behavior (e.g. bending modulus and osmotic pressure) of the sEVs in response to the mechanical stimuli during malignant transformation was not taken into account.

Recently, a research team led by Profs. Zhu Ling, Profs. Yang Yanlian and Profs. Wang Chen from the National Center for Nanoscience and Technology studied the sEVs at single vesicle level by nanoindentation on AFM and explore their correlation with tumor malignancy. This work was published in Advanced Science (2021, DOI: 10.1002/advs.202100825).

Here researchers quantitatively characterize the nanomechanical signatures of breast cancer-derived sEVs, exploring their relationship with tumor malignancy and different size ranges. Researchers also demonstrated that the stiffness of the sEVs is determined by the combined contribution of the bending modulus and osmotic pressure of the sEVs. The bending modulus decreases with increasing malignancy of the sEVs and is lower in the sEVs with smaller sizes, while the stiffness and osmotic pressure increase with increasing malignancy of the sEVs and decrease with increasing sizes of the sEVs. This study contributes to establish comprehensive communication between the nanomechanical signatures of the sEVs and tumor malignancy, which provide potential diagnostic markers of cancer and help to understand the role of cancer mechanobiology in tumor progression and metastasis. Moreover, the sEVs have attracted increasing attention as drug delivery vehicles due to their high biocompatibility, low immunogenicity, and their ability to cross the biological barriers. Nanomechanical characterization of the sEVs provides important information for the optimization of the engineered sEVs to enhance drug delivery efficiency.

The research team led by Profs.Yang Yanlian has been committed to the development of new methods for tumor detection and treatment for a long time. The researchers established an assessment for the detection and molecular phenotyping of tumor-derived-sEVs based on microbead-assisted flow cytometry and validated the clinical utility of this method in breast cancer (Small methods. 2018;2(11):1800122), glioma (Theranostics, 2019;9(18): 5347-58), pituitary tumors (Analytical Chemistry, 2019;91(15): 9580-89) and other tumor detection, achieving clinical diagnosis and molecular typing of a variety of cancers with high sensitivity and specificity. Based on the classification of landmark protein of tumor-derived sEVs, considering the differences in the nanomechanical properties of sEVs in tumor metastasis, the researchers tended to look for a proper model to extract the mechanical properties of the sEVs from the Force-Indentation-Curves obtained from nanoindentation. This study successfully realized the analysis of nanomechanical properties of vesicles of different malignancy and different sizes, giving insights into the development of diagnostic markers and therapeutics based on cancer mechanobiology.

This work was supported by grants from the National Key Research and Development Program of China, the Strategic Priority Research Program of Chinese Academy of Science, National Natural Science Foundation of China, Key Research Program of Frontier Sciences and Youth Innovation Promotion Association of Chinese Academy of Science.



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