Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK; Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
Cell. 2019 Feb 7;176(4):757-774.e23. doi: 10.1016/j.cell.2018.12.038. Epub 2019 Jan 31.
ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206CD163 tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.
ROCK-Myosin II 驱动癌症细胞在转移扩散过程中快速圆形阿米巴样迁移。对人类黑色素瘤活检的分析表明，在靠近 CD206CD163 肿瘤相关巨噬细胞和血管的原发性肿瘤侵袭前沿，具有高肌球蛋白 II 活性的阿米巴样黑色素瘤细胞占优势。蛋白质组学分析表明，阿米巴样癌细胞中的 ROCK-Myosin II 活性控制着免疫调节分泌组，能够招募单核细胞并将其分化为促进肿瘤的巨噬细胞。阿米巴样癌细胞及其相关巨噬细胞均支持异常血管生成，最终促进肿瘤进展。从机制上讲，阿米巴样癌细胞通过 ROCK-Myosin II 驱动的 IL-1α 分泌和 NF-κB 激活来维持其行为。通过一系列肿瘤模型，我们表明肿瘤细胞中高肌球蛋白 II 活性重塑先天免疫微环境以支持肿瘤生长。我们描述了肌球蛋白 II 动力学在癌细胞中通过分泌因子控制髓样细胞功能的意外作用。
