Qiu Yaqi, Luan Guangxin, Liu Yiwen, He Yiqing, Zhang Guoliang, Guo Qian, Yang Cuixia, Du Yan, Gao Feng
Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Biol Chem. 2025 Jun;301(6):110264. doi: 10.1016/j.jbc.2025.110264. Epub 2025 May 21.
Luminal type breast cancer (BrCa) cells invade into the surrounding tissues as collective strands, making them more metastatic than single cells. We have previously reported that the leading subpopulation of collective cells expressed high levels of CD44, which was associated with enhanced migratory and invasive potential of BrCa. It is crucial to elucidate how CD44 becomes enriched in leader cells and contributes to collective migration. In this study, we aimed to uncover the mechanisms responsible for CD44 upregulation in this context. First, we demonstrated that CD44 could facilitate dynamic lamellipodia formation by interacting with cytoskeletal proteins through its cytoplasmic domain. Then, we identified that a transcriptional regulator, Sin3a, was remarkably upregulated at the front edge of collectively migrating cells, exhibiting a correlation with enhanced CD44 expression. Notably, the knockdown of Sin3a effectively suppressed CD44 enrichment and lamellipodia outgrowth in leader cells, resulting in a significantly decreased cohesive movement of BrCa cells in vitro and in vivo. Our findings suggested that Sin3a was a novel regulator in CD44-facilitated lamellipodia formation and subsequent collective migration. This study elucidated the molecular mechanism underlying CD44 upregulation during collective migration of luminal-type BrCa cells, providing potential therapeutic targets to prevent cancer metastasis.
管腔型乳腺癌（BrCa）细胞以集体条索状侵入周围组织，使其比单细胞更具转移性。我们之前报道过，集体细胞中的主导亚群表达高水平的CD44，这与BrCa增强的迁移和侵袭潜能相关。阐明CD44如何在领头细胞中富集并促进集体迁移至关重要。在本研究中，我们旨在揭示在这种情况下负责CD44上调的机制。首先，我们证明CD44可通过其胞质结构域与细胞骨架蛋白相互作用，促进动态片状伪足的形成。然后，我们发现一种转录调节因子Sin3a在集体迁移细胞的前沿显著上调，与增强的CD44表达相关。值得注意的是，敲低Sin3a可有效抑制领头细胞中CD44的富集和片状伪足的生长，导致体外和体内BrCa细胞的黏附运动显著减少。我们的研究结果表明，Sin3a是CD44促进片状伪足形成及随后集体迁移的新型调节因子。本研究阐明了管腔型BrCa细胞集体迁移过程中CD44上调的分子机制，为预防癌症转移提供了潜在的治疗靶点。
