Shalarria Cooper, Molly Matthews, Michael Knight, Sharmila Sridhar, Anna Sorace, Lalita A Shevde, M K Sewell-Loftin
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A second series of studies utilized magnetic beads to generate strains in the model without secretion of growth factors. Microtissues were analyzed for TNBC migration and proliferation via Ki67 staining.</p><p><strong>Results: </strong>TNBC cells migrated significantly more towards CAFs compared to NBFs (5×); TME models with magnetic beads showed a 2× increase in migration compared to no strain controls. TNBC cells treated with shRNA against VEGFR-2 demonstrated decreased overall migration but still significantly more towards CAFs vs. NBFs (2×). Proliferation analyses showed strain significantly increased Ki67 in control cells (10%+ vs. 28%+) but not in shVEGFR-2 TNBC (~ 10% all conditions).</p><p><strong>Discussion: </strong>These studies demonstrate that strain in the TME drives increased migration and proliferation of TNBC. Loss of VEGFR-2 suppresses migration and growth, even with mechanical stimulation. Therefore, our results suggest that mechanosignaling via VEGFR-2 on TNBC may regulate disease progression and potentially explain failure of anti-VEGFR-2 drugs in breast cancer patients.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s12195-025-00866-x.</p>","PeriodicalId":9687,"journal":{"name":"Cellular and molecular bioengineering","volume":"18 5","pages":"473-488"},"PeriodicalIF":3.5000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12579648/pdf/","citationCount":"0","resultStr":"{\"title\":\"Strain Promotes Triple Negative Breast Cancer Proliferation and Migration Via VEGFR-2.\",\"authors\":\"Shalarria Cooper, Molly Matthews, Michael Knight, Sharmila Sridhar, Anna Sorace, Lalita A Shevde, M K Sewell-Loftin\",\"doi\":\"10.1007/s12195-025-00866-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Triple negative breast cancer (TNBC) has significantly worse outcomes compared to other subtypes. 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引用次数: 0
摘要
与其他亚型相比，三阴性乳腺癌（TNBC）的预后明显更差。肿瘤微环境（TME）中由癌症相关成纤维细胞（CAFs）产生的菌株可以调节TNBC的进展。最近的研究表明，TNBC上VEGFR-2的表达与存活率降低有关，而我们之前的研究表明，菌株激活VEGFR-2来驱动血管生成。我们假设TNBC上的VEGFR-2可以通过机械激活来改变迁移和增殖。方法：将MDA-MB-231 TNBC细胞装入多显微组织TME模型的中心室；相对侧室装载CAFs或正常乳腺成纤维细胞（NBFs）。第二个系列研究利用磁珠在不分泌生长因子的情况下在模型中产生菌株。通过Ki67染色分析显微组织TNBC的迁移和增殖情况。结果：与NBFs相比，TNBC细胞向CAFs的迁移明显更多（5倍）；与没有应变控制相比，带有磁珠的TME模型的迁移量增加了2倍。用shRNA对抗VEGFR-2处理的TNBC细胞显示出总体迁移减少，但对CAFs的迁移仍明显多于对NBFs的迁移（2x）。增殖分析显示，该菌株在对照细胞中显著增加Ki67 (10%+ vs. 28%+)，但在shVEGFR-2 TNBC细胞中没有增加Ki67（所有条件下均为~ 10%）。讨论：这些研究表明，TME中的菌株促进了TNBC的迁移和增殖。即使在机械刺激下，VEGFR-2的缺失也会抑制迁移和生长。因此，我们的研究结果表明，TNBC上通过VEGFR-2的机械信号传导可能调节疾病进展，并可能解释抗VEGFR-2药物在乳腺癌患者中的失败。补充信息：在线版本包含补充资料，提供地址为10.1007/s12195-025-00866-x。
Strain Promotes Triple Negative Breast Cancer Proliferation and Migration Via VEGFR-2.
Introduction: Triple negative breast cancer (TNBC) has significantly worse outcomes compared to other subtypes. Strains in the tumor microenvironment (TME) generated by cancer-associated fibroblasts (CAFs) can regulate TNBC progression. Recent studies suggest that expression of VEGFR-2 on TNBC is linked to decreased survival, while our prior studies show strains activate VEGFR-2 to drive angiogenesis. We hypothesized that VEGFR-2 on TNBC can be mechanically activated to alter migration and proliferation.
Methods: We utilized MDA-MB-231 TNBC cells loaded into the center chamber of a multi-microtissue TME model; opposing side chambers were loaded with CAFs or normal breast fibroblasts (NBFs). A second series of studies utilized magnetic beads to generate strains in the model without secretion of growth factors. Microtissues were analyzed for TNBC migration and proliferation via Ki67 staining.
Results: TNBC cells migrated significantly more towards CAFs compared to NBFs (5×); TME models with magnetic beads showed a 2× increase in migration compared to no strain controls. TNBC cells treated with shRNA against VEGFR-2 demonstrated decreased overall migration but still significantly more towards CAFs vs. NBFs (2×). Proliferation analyses showed strain significantly increased Ki67 in control cells (10%+ vs. 28%+) but not in shVEGFR-2 TNBC (~ 10% all conditions).
Discussion: These studies demonstrate that strain in the TME drives increased migration and proliferation of TNBC. Loss of VEGFR-2 suppresses migration and growth, even with mechanical stimulation. Therefore, our results suggest that mechanosignaling via VEGFR-2 on TNBC may regulate disease progression and potentially explain failure of anti-VEGFR-2 drugs in breast cancer patients.
Supplementary information: The online version contains supplementary material available at 10.1007/s12195-025-00866-x.
期刊介绍：
The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas:
Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example.
Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions.
Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress.
Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.
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