Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China.
Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
Adv Sci (Weinh). 2023 Dec;10(35):e2305550. doi: 10.1002/advs.202305550. Epub 2023 Oct 12.
Effective treatment for metastasis, a leading cause of cancer-associated death, is still lacking. To seed on a distal organ, disseminated cancer cells (DCCs) must adapt to the local tissue microenvironment. However, it remains elusive how DCCs respond the pro-metastatic niche signals. Here, systemic motif-enrichment identified myocyte enhancer factor 2D (MEF2D) as a critical sensor of niche signals to regulate DCCs adhesion and colonization, leading to intrahepatic metastasis and recurrence of liver cancer. In this context, MEF2D transactivates Itgb1 (coding β1-integrin) and Itgb4 (coding β4-integrin) to execute temporally unique functions, where ITGB1 recognizes extracellular matrix for early seeding, and ITGB4 acts as a novel sensor of neutrophil extracellular traps-DNA (NETs-DNA) for subsequent chemotaxis and colonization. In turn, an integrin-FAK circuit promotes a phosphorylation-dependent USP14-orchastrated deubiquitination switch to stabilize MEF2D via circumventing degradation by the E3-ubiquitin-ligase MDM2. Clinically, the USP14(pS432)-MEF2D-ITGB1/4 feedback loop is often hyper-active and indicative of inferior outcomes in human malignancies, while its blockade abrogated intrahepatic metastasis of DCCs. Together, DCCs exploit a deubiquitination-dependent switch on MEF2D to integrate niche signals in the liver mesenchyme, thereby amplifying the pro-metastatic integrin-FAK signaling. Disruption of this feedback loop is clinically applicable with fast-track potential to block microenvironmental cues driving metastasis.
有效的转移性治疗方法（转移性是癌症相关死亡的主要原因）仍然缺乏。为了在远端器官上播种，扩散的癌细胞 (DCC) 必须适应局部组织微环境。然而，DCC 如何响应促转移生态位信号仍然难以捉摸。在这里，系统基序富集鉴定出肌细胞增强因子 2D (MEF2D) 作为生态位信号的关键传感器，以调节 DCCs 的黏附和定植，导致肝癌的肝内转移和复发。在这种情况下，MEF2D 转录激活 Itgb1（编码β1-整合素）和 Itgb4（编码β4-整合素）以执行具有时间特异性的功能，其中 ITGB1 识别细胞外基质以进行早期播种，而 ITGB4 作为中性粒细胞细胞外陷阱-DNA（NETs-DNA）的新型传感器，用于随后的趋化作用和定植。反过来，整合素-FAK 回路促进了一个依赖于磷酸化的 USP14 调控的去泛素化开关，通过绕过 E3 泛素连接酶 MDM2 的降解来稳定 MEF2D。临床上，USP14(pS432)-MEF2D-ITGB1/4 反馈回路通常过度活跃，并且是人类恶性肿瘤预后不良的标志，而其阻断可消除 DCCs 的肝内转移。总之，DCC 利用 MEF2D 上的去泛素化依赖开关来整合肝间质中的生态位信号，从而放大促转移的整合素-FAK 信号。破坏这种反馈回路具有临床应用潜力，可以快速阻断驱动转移的微环境线索。
