Zhu Yalun, Abedini Atefeh, Rodriguez Galaxia M, McCloskey Curtis W, Abou-Hamad John, Salah Omar Salah, Larocque Janie, Tsoi Mayra F, Boerboom Derek, Cook David, Vanderhyden Barbara
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Oncogene. 2025 Apr 12. doi: 10.1038/s41388-025-03387-z.
High-grade serous ovarian cancer (HGSOC) is the deadliest and most common subtype of ovarian cancer. Unfortunately, most patients develop recurrence and, ultimately, resistance to standard platinum chemotherapy. Large tumor suppressors LATS1 and LATS2, the core Hippo signaling kinases, have been implicated in various cancer types, including ovarian cancer. The mechanism by which LATS1/2 suppresses ovarian cancer progression is currently elusive, but the expression of LATS1/2 is frequently reduced or lost in these cancers. In this study, we demonstrate that the inactivation of LATS1/2 is sufficient to transform normal mouse ovarian epithelium into tumorigenic cells associated with increased cell proliferation, invasion, and stemness and epithelial-mesenchymal transition (EMT) characteristics. The knockout of Lats1/2 in the epithelial cells also leads to higher expression levels of the immune checkpoint molecule PD-L1, suggesting a regulatory role of LATS1/2 in modulating immune responses and immune evasion. In addition to the loss of LATS1/2 activating the downstream transcriptional coactivators YAP and TAZ, PI3K-AKT activity was also increased, likely contributing to enhanced tumor proliferation and survival. The stimulatory effect of Lats1/2 knockout on cell proliferation can be partially reversed by treatment with the AKT inhibitor MK2206. Treatment with verteporfin, a potent inhibitor of YAP/TAZ, decreases ovarian tumor progression and reduces the activated AKT in the tumors. In summary, this study uncovers several biological mechanisms for the initiation of HGSOC and identifies LATS1/2 as potential prognostic indicators and therapeutic targets.
高级别浆液性卵巢癌（HGSOC）是卵巢癌中最致命且最常见的亚型。不幸的是，大多数患者会出现复发，最终对标准铂类化疗产生耐药性。大型肿瘤抑制因子LATS1和LATS2是核心的Hippo信号激酶，已在包括卵巢癌在内的多种癌症类型中有所涉及。目前尚不清楚LATS1/2抑制卵巢癌进展的机制，但在这些癌症中LATS1/2的表达常常降低或缺失。在本研究中，我们证明LATS1/2的失活足以将正常小鼠卵巢上皮转化为具有肿瘤发生能力的细胞，这些细胞具有细胞增殖、侵袭增加以及干性和上皮-间质转化（EMT）特征。上皮细胞中Lats1/2的敲除还导致免疫检查点分子PD-L1的表达水平升高，这表明LATS1/2在调节免疫反应和免疫逃逸中具有调节作用。除了LATS1/2的缺失激活下游转录共激活因子YAP和TAZ外，PI3K-AKT活性也增加，这可能有助于增强肿瘤增殖和存活。用AKT抑制剂MK2206处理可部分逆转Lats1/2敲除对细胞增殖的刺激作用。用YAP/TAZ的强效抑制剂维替泊芬处理可降低卵巢肿瘤进展并降低肿瘤中激活的AKT水平。总之，本研究揭示了HGSOC起始的几种生物学机制，并将LATS1/2确定为潜在的预后指标和治疗靶点。
