Epitranscriptional regulation of TGF-β pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.
Epitranscriptional regulation of TGF-β pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.
复制标题
通过m6 A/YTHDF 2对TGF-β假受体BAMBI的表位调控驱动外源性辐射抗性。
DOI：
10.1172/jci172919
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发表时间：
2023-12-15
影响因子：
15.9
通讯作者：
Weichselbaum, Ralph
中科院分区：
文献类型：
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作者：
Wang, Liangliang;Si, Wei;Yu, Xianbin;Piffko, Andras;Dou, Xiaoyang;Ding, Xingchen;Bugno, Jason;Yang, Kaiting;Wen, Chuangyu;Zhang, Linda;Chen, Dapeng;Huang, Xiaona;Wang, Jiaai;Arina, Ainhoa;Pitroda, Sean;Chmura, Steven J.;He, Chuan;Liang, Hua Laura;Weichselbaum, Ralph
TGF-β信号的激活是一种限制放射治疗潜力的外在抗性机制。骨形态发生蛋白和激活素膜结合抑制剂（BAMBI）拮抗TGF-β信号并与癌症进展有关。然而，BAMBI在免疫细胞中的调控分子机制及其对辐射后抗肿瘤免疫的影响尚不明确。在这里，我们发现电离辐射（IR）在小鼠模型和人类模型中特异性地降低了BAMBI在免疫抑制性髓源性抑制细胞（MDSCs）中的表达。在机制上，YTH n6 -甲基腺苷rna结合蛋白F2 （YTHDF2）以n6 -甲基腺苷依赖（m6a依赖）的方式直接结合并降解Bambi转录本，这依赖于NF-κB信号传导。BAMBI通过抑制TGF-β信号通路抑制MDSCs的肿瘤浸润能力和抑制功能。腺相关病毒将小鹿斑比（AAV-Bambi）递送到肿瘤微环境中，增强了放射治疗和放射免疫治疗联合的抗肿瘤作用。有趣的是，AAV-Bambi与IR联合使用不仅可以改善肿瘤的局部控制，还可以抑制远处转移，进一步支持其临床翻译潜力。我们的发现揭示了BAMBI在髓细胞中的惊人作用，揭示了克服外源性放射耐药的潜在治疗策略。
Activation of TGF-β signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-β signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine–dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-β signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.