Institute of Biomedicine and FICAN West Cancer Centre Laboratory, University of Turku, 20520 Turku, Finland; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Åbo Akademi University, Faculty of Science and Engineering, Biosciences, 20520 Turku, Finland; Turku Bioimaging, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, Åbo Akademi University, 20520 Turku, Finland.
Dev Cell. 2022 Oct 24;57(20):2350-2364.e7. doi: 10.1016/j.devcel.2022.09.016.
Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer. During invasion, the encapsulating DCIS basement membrane (BM) is compromised, and tumor cells invade the surrounding stroma. The mechanisms that regulate functional epithelial BMs in vivo are poorly understood. Myosin-X (MYO10) is a filopodia-inducing protein associated with metastasis and poor clinical outcome in invasive breast cancer (IBC). We identify elevated MYO10 expression in human DCIS and IBC, and this suggests links with disease progression. MYO10 promotes filopodia formation and cell invasion in vitro and cancer-cell dissemination from progressively invasive human DCIS xenografts. However, MYO10-depleted xenografts are more invasive. These lesions exhibit compromised BMs, poorly defined borders, and increased cancer-cell dispersal and EMT-marker-positive cells. In addition, cancer spheroids are dependent on MYO10-filopodia to generate a near-continuous extracellular matrix boundary. Thus, MYO10 is protective in early-stage breast cancer, correlating with tumor-limiting BMs, and pro-invasive at later stages, facilitating cancer-cell dissemination.
导管原位癌 (DCIS) 是乳腺癌的一种早期侵袭阶段。在侵袭过程中，包裹性的 DCIS 基底膜 (BM) 被破坏，肿瘤细胞侵袭周围基质。调节体内功能性上皮 BM 的机制还知之甚少。肌球蛋白-X (MYO10) 是一种与侵袭性乳腺癌 (IBC) 转移和不良临床结局相关的诱导纤毛形成蛋白。我们在人 DCIS 和 IBC 中发现了升高的 MYO10 表达，这表明它与疾病进展有关。MYO10 在体外促进纤毛形成和细胞侵袭，以及从逐渐侵袭性的人 DCIS 异种移植物中促进癌细胞扩散。然而， MYO10 耗尽的异种移植物更具侵袭性。这些病变表现出 BM 受损、边界不清晰、癌细胞分散和 EMT 标志物阳性细胞增加。此外，癌症球体依赖 MYO10 纤毛来生成近乎连续的细胞外基质边界。因此，MYO10 在早期乳腺癌中具有保护作用，与肿瘤限制的 BM 相关，在后期则促进侵袭，促进癌细胞扩散。
