PO.MCB03.03 · 分子与细胞生物学
柔软的细胞外基质通过触发RNF146介导的AMOT降解和YAP/TAZ驱动的巨噬细胞衰老来协调胃癌进展
Soft extracellular matrix orchestrates gastric cancer progression by triggering RNF146-mediated AMOT degradation and YAP/TAZ-driven senescence in macrophages
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摘要 Abstract
中文摘要
肿瘤微环境（TME）的力学特性是癌症进展的关键调控因素。虽然坚硬细胞外基质（ECM）的作用已得到充分确立，但在早期或重塑肿瘤中常见的柔软ECM如何调节胃癌的免疫功能仍不明确。本研究揭示了一条完整的力学-免疫学通路，其中柔软ECM通过在肿瘤相关巨噬细胞（TAM）中诱导促肿瘤发生的衰老来驱动肿瘤发生。我们证明，柔软ECM通过细胞骨架重塑和F-actin解聚来启动这一级联反应，从而将血管生成素（AMOT）从肌动蛋白网络中置换出来，增加其胞质池。释放出来的AMOT随后被E3泛素连接酶RNF146特异性靶向，RNF146在TAM中响应柔软力学信号而上调，导致AMOT泛素化和蛋白酶体降解。这种降解解除了对YAP/TAZ的胞质隔离，使其能够在TAM内发生核转位和转录激活。这种力学化学重编程启动了一种独特的衰老相关分泌表型（SASP），其特征是CCL2、IL-8、MMP-12和TGF-beta的分泌升高，它们共同促进肿瘤细胞侵袭、血管生成和免疫抑制。使用共培养实验和原位胃癌模型进行的功能验证证实，RNF146介导的AMOT缺失足以诱导衰老并加速肿瘤生长和转移。相反，髓系特异性RNF146敲除可稳定AMOT，抑制SASP，并有力地抑制肿瘤进展。因此，我们的发现描绘了胃癌中一条完整的病理轴：从柔软ECM感知和细胞骨架重塑，到RNF146介导的被置换AMOT降解、YAP/TAZ驱动的巨噬细胞衰老，最终导致肿瘤进展。这项工作通过在机制上将柔软ECM与促肿瘤发生的免疫衰老联系起来，解决了癌症中柔软ECM长期存在的悖论，并提名RNF146-AMOT轴作为一个新颖且有前景的基质治疗干预靶点。
查看英文原文 English abstract
The mechanical properties of the tumor microenvironment (TME) are critical regulators of cancer progression. While the role of a stiff extracellular matrix (ECM) is well-established, how soft ECM-common in early or remodeled tumors-modulates immune function in gastric cancer remains elusive. This study unveils a complete mechano-immunological pathway wherein soft ECM drives tumorigenesis by inducing pro-tumorigenic senescence in tumor-associated macrophages (TAMs). We demonstrate that soft ECM initiates this cascade through cytoskeletal remodeling and F-actin depolymerization, which displaces Angiomotin (AMOT) from the actin network, increasing its cytoplasmic pool. The liberated AMOT is then specifically targeted by the E3 ubiquitin ligase RNF146, which is upregulated in TAMs in response to soft mechanical cues, leading to AMOT ubiquitination and proteasomal degradation. This degradation relieves the cytoplasmic sequestration of YAP/TAZ, enabling their nuclear translocation and transcriptional activation within TAMs. This mechanochemical reprogramming initiates a distinct senescence-associated secretory phenotype (SASP), characterized by elevated secretion of CCL2, IL-8, MMP-12, and TGF-beta, which collectively promote tumor cell invasion, angiogenesis, and immunosuppression. Functional validation using co-culture assays and orthotopic gastric cancer models confirmed that RNF146-mediated AMOT loss is sufficient to induce senescence and accelerate tumor growth and metastasis. Conversely, myeloid-specific RNF146 knockout stabilized AMOT, suppressed the SASP, and potently inhibited tumor progression. Our findings thereby delineate a complete pathological axis in gastric cancer: from soft ECM sensing and cytoskeletal remodeling to RNF146-mediated degradation of displaced AMOT, YAP/TAZ-driven macrophage senescence, and ultimately tumor progression. This work resolves the long-standing paradox of soft ECM in cancer by mechanistically linking it to pro-tumorigenic immune senescence, and nominates the RNF146-AMOT axis as a novel and promising stromal target for therapeutic intervention.
利益披露 Disclosure
G. Deng, None..
Y. Luo, None..
Y. Pan, None..
Y. Zhang, None..
Y. Lin, None..
F. Wang, None..
J. Wang, None..
S. Fang, None.