Riehl Brandon D, Kim Eunju, Boudreaux Taylor, Ovando Osaira, Vielmas-Duarte Stephanie, Choi Suyong, Band Hamid, Mei Lanju, Dutta Diganta, Chandra Surabhi, Lim Jung Yul
Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
Department of Biology, University of Nebraska at Kearney, Kearney, NE 68849, USA.
bioRxiv. 2025 May 27:2025.05.22.655615. doi: 10.1101/2025.05.22.655615.
We tested how the diabetes-related hyperglycemic condition affects the migration of highly metastatic triple-negative breast cancer (TNBC) cells, MDA-MB-231, under a physiological fluid shear environment. MDA-MB-231 cells displayed a significantly enhanced migratory behavior under a high glucose condition (25 mM) specifically when exposed to flow at 15 dyne/cm shear stress. In contrast, the effect of fluid shear was marginal under low glucose (5 mM). Normal epithelial MCF-10A cells, on the other hand, showed increased migration by fluid shear under both low and high glucose conditions. The fluid shear-triggered MDA-MB-231 cell migration under high glucose was significantly abrogated by a focal adhesion kinase (FAK) inhibitor, supporting the mediatory role of FAK in MDA-MB-231 TNBC cell sensing of the high glucose-fluid shear environment during migration. The role of FAK was further demonstrated by the effects of FAK inhibitor on MDA-MB-231 cell migration in scratch wound healing and Boyden chamber migration assays. Our studies provide evidence that high glucose and fluid shear could jointly trigger MDA-MB-231 TNBC cell migration that requires FAK activity. These may provide improved mechanistic insights into how concurrent diabetes may impact the pro-metastatic behavior of breast cancer and suggest the impact of exploring FAK as a relevant therapeutic target.
我们测试了糖尿病相关的高血糖状况如何在生理流体剪切环境下影响高转移性三阴性乳腺癌（TNBC）细胞MDA-MB-231的迁移。MDA-MB-231细胞在高糖条件（25 mM）下，特别是当暴露于15达因/平方厘米剪切应力的流动时，表现出显著增强的迁移行为。相比之下，在低糖（5 mM）条件下，流体剪切的影响很小。另一方面，正常上皮MCF-10A细胞在低糖和高糖条件下均表现出流体剪切诱导的迁移增加。高糖条件下流体剪切触发的MDA-MB-231细胞迁移被粘着斑激酶（FAK）抑制剂显著消除，这支持了FAK在MDA-MB-231 TNBC细胞迁移过程中对高糖-流体剪切环境感知的介导作用。FAK抑制剂对MDA-MB-231细胞在划痕愈合和Boyden小室迁移试验中的迁移影响进一步证明了FAK的作用。我们的研究提供了证据，表明高糖和流体剪切可共同触发MDA-MB-231 TNBC细胞迁移，这需要FAK活性。这些研究可能为并发糖尿病如何影响乳腺癌的促转移行为提供更好的机制见解，并提示探索FAK作为相关治疗靶点的影响。
