Department of Oncology, University of Torino, Candiolo, Italy.
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
Cancer Res. 2019 Nov 15;79(22):5884-5896. doi: 10.1158/0008-5472.CAN-19-1166. Epub 2019 Oct 4.
Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein-Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/ genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell-intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell-intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis. SIGNIFICANCE: This study reports a multilevel platform of gastric cancer PDXs and identifies a MSI gastric signature that could contribute to the advancement of precision medicine in gastric cancer.
胃癌是全球癌症死亡的第三大主要原因。尽管治疗有了显著改善，但晚期胃癌患者的临床预后仍然较差；因此，从临床角度来看，鉴定和验证新的靶点非常重要。我们生成了一个广泛的胃癌模型多层次平台，包括 100 个患者来源的异种移植物（PDX）、原代细胞系和类器官。根据组织学、微卫星稳定性、EB 病毒状态和分子特征对样本进行分类。这个 PDX 平台是在学术机构中最广泛的，它包括了癌症基因组图谱（TCGA）确定的所有胃癌组织学和分子类型。PDX 的组织病理学特征与患者的原发性肿瘤一致，并在小鼠体内传代过程中得以维持。调节移植物率的因素包括组织学、TNM 分期、酪氨酸激酶/基因的拷贝数增益和微卫星稳定性状态。PDX 和 PDX 衍生的细胞/类器官对于研究靶向治疗反应具有潜在的用处。最后，PDX 转录组分析确定了一个肿瘤细胞内在的微卫星不稳定性（MSI）特征，该特征有效地被导入胃癌中，使得在微卫星稳定（MSS）患者中，可以识别出一组具有共同分子特征和显著更好预后的 MSI 样肿瘤。总之，我们生成了一个广泛的胃癌 PDX 平台，其开发将有助于鉴定和验证新的“可成药”靶点，并优化治疗策略。此外，对胃癌 PDX 的转录组分析确定了一个肿瘤细胞内在的 MSI 特征，识别出一组具有 MSI 转录特征的 MSS 患者，具有更好的预后。意义：本研究报告了一个胃癌 PDX 的多层次平台，并确定了一个 MSI 胃癌特征，这可能有助于推进胃癌的精准医学。
