Migrasome-mediated clearance of excess PLK4 defines a targetable vulnerability

作者：Jihong Ma, Yuhan Guo, Yuening Jiang, Qilong Wang, Meiyu Bi, Tianzhen Wang, Yinan Xiao, Na Zhang, Pan Wang, Yu Wu, Bingteng Xie, Gang Wang, Mo Li · 发表于：EBioMedicine · 年份：2026 · DOI：10.1016/j.ebiom.2026.106237 · 被引用次数：1 · 研究领域：Microtubule and mitosis dynamics、Cellular transport and secretion、Ubiquitin and proteasome pathways

BACKGROUND: Centrosome amplification caused by Polo-like kinase 4 (PLK4) overexpression promotes tumour initiation, yet sustained PLK4 accumulation is detrimental to cancer cell viability. While proteasomal degradation limits PLK4 levels, whether alternative clearance mechanisms exist remains unknown. METHODS: We established inducible PLK4-overexpressing breast cancer cells and employed live-cell imaging, vesicular marker profiling, immunoprecipitation-mass spectrometry, and in vivo patient-derived xenograft models to investigate how cancer cells eliminate excess PLK4. FINDINGS: In this study, we identified a previously unrecognised mechanism in which excess PLK4 is rapidly expelled via migrasomes. The tetraspanin protein TSPAN6 directly binds PLK4 with high affinity and mediates its incorporation into migrasomes for extracellular release. In breast cancer samples, PLK4 expression decreased while TSPAN6 increased during progression. TSPAN6 knockdown blocked PLK4 expulsion, leading to multipolar spindle formation, apoptosis, and suppression of tumour growth and metastasis in vivo. INTERPRETATION: Migrasome-mediated clearance represents a non-proteasomal pathway maintaining centrosome homoeostasis in cancer cells. Targeting TSPAN6 to prevent PLK4 elimination selectively triggers mitotic catastrophe in PLK4-high tumours, highlighting a previously unrecognised therapeutic vulnerability. FUNDING: This work was supported by the National Natural Science Foundation of China (NSFC) (T...