Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Sci Adv. 2024 Mar 15;10(11):eadk0785. doi: 10.1126/sciadv.adk0785. Epub 2024 Mar 13.
Cell migration is a critical contributor to metastasis. Cytokine production and its role in cancer cell migration have been traditionally associated with immune cells. We find that the histone methyltransferase Mixed-Lineage Leukemia 1 (MLL1) controls 3D cell migration via cytokines, IL-6, IL-8, and TGF-β1, secreted by the cancer cells themselves. MLL1, with its scaffold protein Menin, controls actin filament assembly via the IL-6/8/pSTAT3/Arp3 axis and myosin contractility via the TGF-β1/Gli2/ROCK1/2/pMLC2 axis, which together regulate dynamic protrusion generation and 3D cell migration. MLL1 also regulates cell proliferation via mitosis-based and cell cycle-related pathways. Mice bearing orthotopic MLL1-depleted tumors exhibit decreased lung metastatic burden and longer survival. MLL1 depletion leads to lower metastatic burden even when controlling for the difference in primary tumor growth rates. Combining MLL1-Menin inhibitor with paclitaxel abrogates tumor growth and metastasis, including preexistent metastasis. These results establish MLL1 as a potent regulator of cell migration and highlight the potential of targeting MLL1 in patients with metastatic disease.
细胞迁移是转移的关键贡献者。细胞因子的产生及其在癌细胞迁移中的作用传统上与免疫细胞有关。我们发现组蛋白甲基转移酶混合谱系白血病 1（MLL1）通过癌细胞自身分泌的细胞因子 IL-6、IL-8 和 TGF-β1 控制 3D 细胞迁移。MLL1 与其支架蛋白 Menin 通过 IL-6/8/pSTAT3/Arp3 轴控制肌动蛋白丝组装，并通过 TGF-β1/Gli2/ROCK1/2/pMLC2 轴控制肌球蛋白收缩，共同调节动态突出生成和 3D 细胞迁移。MLL1 还通过有丝分裂相关和细胞周期相关途径调节细胞增殖。携带原位 MLL1 耗尽肿瘤的小鼠表现出肺转移负担降低和存活时间延长。即使控制原发性肿瘤生长速度的差异，MLL1 耗竭也会导致较低的转移负担。将 MLL1-Menin 抑制剂与紫杉醇联合使用可阻断肿瘤生长和转移，包括先前存在的转移。这些结果确立了 MLL1 作为细胞迁移的有效调节剂，并强调了在转移性疾病患者中靶向 MLL1 的潜力。
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