A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell–Intrinsic Transcriptional MSI Traits

Abstract

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/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential use-fulness 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.

Evaluation of molecular subtypes and clonal selection during establishment of patient-derived tumor xenografts from gastric adenocarcinoma

“…We showed in addition that PDX establishment is dependent of tumor molecular subtypes. In line with previous studies 17,18 , the PDX collection was enriched in models established from MSI tumors (n = 15/27, Fisher´s exact test, p = 0.0002, Table 1). A lower number of PDX were developed from MSS/TP53 − (n = 9/32) and MSS/TP53 + (3/ 21), but none from EMT and EBV-positive tumors.…”

“…Fourthly, our study is focused on one tumor type. However, similar findings have been observed in cell lines and PDX 17,24,[26][27][28] , likely suggesting the existence of such phenomenon and an important consideration in other tumor types and associated tumor model system.…”

<p>Promotion of miR-221-5p on the Sensitivity of Gastric Cancer Cells to Cisplatin and Its Effects on Cell Proliferation and Apoptosis by Regulating DDR1</p>

“…Among malignant tumors, gastric cancer is a common digestive system tumor, and its main treatment methods are surgery and systemic chemotherapy. 13,14 However, since most patients were at late stage when they are diagnosed, they have lost the opportunity of surgery and can only be treated with chemotherapy. Due to the existence of drug resistance to chemotherapy, many patients will suffer from poor or even ineffective treatment, which will further aggravate the disease.…”

PSCA is a target of chimeric antigen receptor T cells in gastric cancer

“…To determine the cytotoxicity of transduced T cells in a more delicate and sensitive way, we genetically modified three target cell lines, BGC-823, MKN-28, and KATO III, to express GFPluciferase. Thus, cell viability could be determined by a luciferase reporter system and an illuminator [21]. We then incubated anti-PSCA CAR-T cells and GFP-T cells with the aforementioned target tumor cell lines at E:T ratios of 2:1, 1:1, 1:2, and 1:4.…”