Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
J Thorac Oncol. 2015 May;10(5):844-851. doi: 10.1097/JTO.0000000000000493.
Malignant mesothelioma (MM) is an aggressive neoplasm causatively associated with exposure to asbestos. MM is rarely responsive to conventional cytotoxic drugs, and the outcome remains dismal. It is, therefore, necessary to identify the signaling pathways that drive MM and to develop new therapeutics specifically targeting the molecules involved.
We performed comprehensive RNA sequencing of 12 MM cell lines and four clinical samples using so-called next-generation sequencers.
We found 15 novel fusion transcripts including one derived from chromosomal translocation between the large tumor suppressor 1 (LATS1) and presenilin-1 (PSEN1) genes. LATS1 is one of the central players of the emerging Hippo signaling pathway. The LATS1-PSEN1 fusion gene product lacked the ability to phosphorylate yes-associated protein and to suppress the growth of a MM cell line. The wild-type LATS1 allele was undetectable in this cell line, indicating two-hit genetic inactivation of its tumor suppressor function. Using pathway-targeted exon sequencing, we further identified a total of 11 somatic mutations in four Hippo pathway genes (neurofibromatosis type 2 [NF2], LATS2, RASSF1, and SAV1) in 35% (8 of 23) of clinical samples. Nuclear staining of yes-associated protein was detected in 55% (24 of 44) of the clinical samples. Expression and/or phosphorylation of the Hippo signaling proteins, RASSF1, Merlin (NF2), LATS1, and LATS2, was frequently absent.
The frequent alterations of Hippo pathway molecules found in this study indicate the therapeutic feasibility of targeting this pathway in patients with MM.
恶性间皮瘤（MM）是一种侵袭性肿瘤，与石棉暴露有关。MM 对常规细胞毒药物反应不佳，预后仍然很差。因此，有必要确定驱动 MM 的信号通路，并开发专门针对涉及分子的新疗法。
我们使用所谓的下一代测序仪对 12 种 MM 细胞系和 4 种临床样本进行了全面的 RNA 测序。
我们发现了 15 种新的融合转录本，包括一种来源于大肿瘤抑制因子 1（LATS1）和早老素-1（PSEN1）基因之间染色体易位的转录本。LATS1 是新兴 Hippo 信号通路的核心成员之一。LATS1-PSEN1 融合基因产物缺乏磷酸化 yes 相关蛋白的能力，并抑制 MM 细胞系的生长。该细胞系中无法检测到野生型 LATS1 等位基因，表明其肿瘤抑制功能的两次遗传失活。通过靶向通路的外显子测序，我们进一步在 4 个 Hippo 通路基因（神经纤维瘤病 2 型 [NF2]、LATS2、RASSF1 和 SAV1）中的 11 个体细胞突变中发现了 35%（23 例中的 8 例）临床样本。在 55%（44 例中的 24 例）的临床样本中检测到 yes 相关蛋白的核染色。Hippo 信号蛋白 RASSF1、Merlin（NF2）、LATS1 和 LATS2 的表达和/或磷酸化经常缺失。
本研究中发现 Hippo 通路分子的频繁改变表明靶向 MM 患者该通路的治疗可行性。
