SOX10 deficiency-mediated LAMB3 upregulation determines the invasiveness of MAPKi-resistant melanoma

SOX10 deficiency-mediated LAMB3 upregulation determines the invasiveness of MAPKi-resistant melanoma
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DOI：
10.1038/s41388-023-02917-x
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发表时间：
2023-12-15
期刊：
ONCOGENE
影响因子：
8
通讯作者：
Shao，Yongping
Shao，Yongping
中科院分区：
医学1区
文献类型：
--
作者：
Han，Shujun;Zhang，Mo;Shao，Yongping

文献摘要

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通过转录重编程介导的表型转换对 MAPK 抑制剂 (MAPKi) 产生适应性抗性的黑色素瘤与增强的转移潜力相关，但这种改善的侵袭性的潜在机制尚未完全阐明。在这项研究中，我们发现 MAPKi 抗性黑色素瘤细胞比亲本细胞更具运动性和侵袭性。我们进一步表明，LAMB3（细胞外基质蛋白 laminin-332 的 β 亚基）在 MAPKi 耐药黑色素瘤细胞中上调，并且 LAMB3-整合素 α3/α6 信号介导耐药细胞的运动和侵袭表型。此外，我们证明 MAPKi 抗性黑色素瘤细胞中 SOX10 缺陷可通过 TGF-β 信号传导驱动 LAMB3 上调。转录组分析和功能研究进一步揭示了 FAK/MMP 轴介导 LAMB3 的促侵袭作用。使用小鼠肺转移模型，我们证明 LAMB3 耗竭会抑制体内 MAPKi 耐药细胞的转移潜力。总之，本研究确定了 SOX10low/TGF-β/LAMB3/FAK/MMPs 信号通路，该信号通路决定了 MAPKi 耐药黑色素瘤细胞的迁移和侵袭特性，并为靶向治疗中联合靶向 LAMB3 以抑制黑色素瘤细胞的转移提供了理论基础。
Melanoma that develops adaptive resistance to MAPK inhibitors (MAPKi) through transcriptional reprograming-mediated phenotype switching is associated with enhanced metastatic potential, yet the underlying mechanism of this improved invasiveness has not been fully elucidated. In this study, we show that MAPKi-resistant melanoma cells are more motile and invasive than the parental cells. We further show that LAMB3, a β subunit of the extracellular matrix protein laminin-332 is upregulated in MAPKi-resistant melanoma cells and that the LAMB3-Integrin α3/α6 signaling mediates the motile and invasive phenotype of resistant cells. In addition, we demonstrate that SOX10 deficiency in MAPKi-resistant melanoma cells drives LAMB3 upregulation through TGF-β signaling. Transcriptome profiling and functional studies further reveal a FAK/MMPs axis mediates the pro-invasiveness effect of LAMB3. Using a mouse lung metastasis model, we demonstrate LAMB3 depletion inhibits the metastatic potential of MAPKi-resistant cells in vivo. In summary, this study identifies a SOX10low/TGF-β/LAMB3/FAK/MMPs signaling pathway that determines the migration and invasion properties of MAPKi-resistant melanoma cells and provide rationales for co-targeting LAMB3 to curb the metastasis of melanoma cells in targeted therapy.