Medical Radiology and Radiation Safety. 2025. Vol. 70. № 2
DOI:10.33266/1024-6177-2025-70-2-9-15
P.A. Malakhov1, M.V. Pustovalova1, A.V. Aleksandrova1, E.G. Kontareva1,
A.V. Smirnova1, Z. Nofal1, A.N. Osipov1, 2, S.V. Leonov1
Repetitive Confined Migration Leads to an Increase in Clonogenic Activity and Chemoresistanse of Human Non-Small Cell Lung Cancer Cells, Regardless of Their Initial Chemo- and Radiosensitivity
1 Moscow Institute of Physics and Technology (National Research University), Dolgoprudny, Russia
2 A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
Contact person: M.V. Pustovalova, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
Purpose: Radiation therapy can treat non-small cell lung cancer (NSCLC), but its effectiveness is limited by the development of tumor radioresistance. Studies have shown that radiation can affect tumor aggressiveness, either reducing or increasing the invasiveness of remaining cancer cells, depending on the cell lines and radiation type. However, the effect of tumor cell migration in the confined porous space of tumor tissue on their phenotypic characteristics is not well understood. This study aimed to investigate how migration in confined spaces affects the phenotypic traits of two NSCLC isogenic cell lines with varying levels of radioresistance, invasiveness, and repopulation ability.
Material and methods: The biophysical impact on the A549 cell line and its isogenic radioresistant subline A549IR was carried out by their sequential triple migration in a limited space of membrane pores with a diameter of 8 μm in Boyden chambers, following the concentration gradient of fetal bovine serum. The ability to repopulate cell populations migrated across membranes was characterized using clonogenic analysis. We assessed markers such as Ki67 (cell cycle activity), vimentin (a cytoskeletal protein linked to migration and metastasis), and fluorescent nanosensor uptake (indicating metastasis potential) through quantitative analysis of digital images from high-content imaging of individual cells. A standard method for determining cell mass with the dye sulphorodamine B after exposure to different concentrations of cisplatin was used to assess the chemosensitivity of tumor cells before and after migration.
Results and Conclusion: The study shows that repeated migration through an 8 μm pore, which simulates conditions cancer cells experience during metastasis, deforms the nuclei of non-small cell lung cancer (NSCLC) cells. This deformation reduces Ki67-related chromatin reorganization and alters gene expression, notably increasing vimentin. This results in increased chemoresistance and a greater likelihood of repopulation and metastasis in these cells, regardless of their initial ability to migrate or their sensitivity to chemotherapy and radiation.
Keywords: non-small cell lung cancer, radioresistance, chemoresistance, confined migration, metastatic activity, endocytosis, nanosensors
For citation: Malakhov PA, Pustovalova MV, Aleksandrova AV, Kontareva EG, Smirnova AV, Nofal Z, Osipov AN, Leonov SV. Repetitive Confined Migration Leads to an Increase in Clonogenic Activity and Chemoresistanse of Human Non-Small Cell Lung Cancer Cells, Regardless of Their Initial Chemo- and Radiosensitivity. Medical Radiology and Radiation Safety. 2025;70(2):9–15. (In Russian). DOI:10.33266/1024-6177-2025-70-2-9-15
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Conflict of interest. The authors declare no conflict of interest.
Financing. The work was supported by the Ministry of Science and Higher Education of the Russian Federation (State Assignment): “Development of local drug delivery systems for medical purposes”, number FSMG-2023-0015, agreement number No. 075-03-2024-117 dated 17.01.2024.
Contribution. Article was prepared with equal participation of the authors.
Article received: 20.12.2024. Accepted for publication: 25.01.2025.