Background: Epithelial-mesenchymal transition (EMT) is prevalent in human cancer and facilitates tumor metastasis and therapy resistance by enhancing cancer cell motility, invasiveness, survival, and immune evasion. However, the molecular mechanisms underlying the cellular changes during EMT remain largely elusive, making it challenging to simultaneously target these diverse malignant phenotypes.Results: Here, we show that the EMT-inducing ZEB transcription factors directly repressed WWC1 (also known as KIBRA), a key upstream activating component of the Hippo signaling pathway. The EMT program thus inherently downregulated WWC1, leading to impaired Hippo signaling and constitutive activation of the downstream effector and transcriptional coactivator YAP. The YAP-dependent transcriptional program promotes manifold cellular phenotypes that resemble those induced during EMT. Indeed, pharmacological inhibition of YAP suppressed EMT-stimulated cell migration and invasion, apoptosis resistance, and cell size growth, identifying active YAP as a common essential mediator of multiple EMT-associated phenotypes. Moreover, YAP activation directly induced transcription of B7 family immune checkpoint proteins VSIR (VISTA) and PD-L2, and rendered cancer cells resistant to effector CD8 T cells.Conclusions: Collectively, the results suggest that EMT intrinsically activates YAP by repressing WWC1, providing a non-genetic mechanism for pervasive YAP activation in cancer. Activated YAP, in turn, critically contributes to diverse EMT-enhanced malignant phenotypes and immune evasion. Therefore, pharmacological targeting of YAP may suppress various EMT-associated malignant properties and improve the efficacy of anti-PD-1 immunotherapy, offering a promising therapeutic strategy against cancer cells exhibiting EMT characteristics.
背景：上皮-间质转化（EMT）在人类癌症中普遍存在，通过增强癌细胞的运动性、侵袭性、存活能力和免疫逃逸能力，促进肿瘤转移和治疗抵抗。然而，EMT过程中细胞变化的分子机制在很大程度上仍不清楚，这使得同时靶向这些多样化的恶性表型具有挑战性。 结果：本研究发现，诱导EMT的ZEB转录因子直接抑制了Hippo信号通路的关键上游激活组分WWC1（亦称KIBRA）。因此，EMT程序本身下调了WWC1，导致Hippo信号受损，并使下游效应因子和转录共激活因子YAP持续激活。YAP依赖的转录程序促进了多种细胞表型，这些表型与EMT诱导的表型相似。实际上，YAP的药理抑制能够抑制EMT刺激的细胞迁移和侵袭、凋亡抵抗以及细胞体积增长，这表明活化的YAP是多种EMT相关表型的共同关键介质。此外，YAP的激活直接诱导了B7家族免疫检查点蛋白VSIR（VISTA）和PD-L2的转录，并使癌细胞对效应性CD8 T细胞产生抵抗。 结论：总体而言，研究结果表明EMT通过抑制WWC1内在激活YAP，为癌症中普遍的YAP激活提供了一种非遗传机制。激活的YAP反过来对多种EMT增强的恶性表型和免疫逃逸起到关键作用。因此，YAP的药理靶向可能抑制多种EMT相关的恶性特性，并提高抗PD-1免疫疗法的疗效，为针对具有EMT特征的癌细胞提供了一种有前景的治疗策略。
Epithelial-Mesenchymal Transition Activates YAP to Drive Malignant Progression and Immune Evasion
肿瘤(癌症)患者之家