Patient-Derived Xenograft Establishment from Human Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor-stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterize MPM patient-derived xenografts (PDX) to determine their suitability as preclinical models and whether tumors that engraft reflect a more aggressive biological phenotype. Fresh tumors were harvested from extrapleural pneumonectomy, decortication, or biopsy samples of 50 MPM patients and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations. We correlated selected mesothelioma biomarkers between PDX and patient tumors, and PDX establishment with the clinical pathologic features of the patients, including their survival. DNA of nine PDXs was profiled using the OncoScan FFPE Express platform. Ten PDXs were treated with cisplatin and pemetrexed. A PDX was formed in 20 of 50 (40%) tumors implanted. Histologically, PDX models closely resembled the parent tumor. PDX models formed despite preoperative chemotherapy and radiotherapy. In multivariable analysis, patients whose tumors formed a PDX had significantly poorer survival when the model was adjusted for preoperative treatment (HR, 2.46; 95% confidence interval, 1.1-5.52; = 0.028). Among 10 models treated with cisplatin, seven demonstrated growth inhibition. Genomic abnormalities seen in nine PDX models were similar to that previously reported. Patients whose tumors form PDX models have poorer clinical outcomes. MPM PDX tumors closely resemble the genotype and phenotype of parent tumors, making them valuable models for preclinical studies. .

Wnt/IL‐1β/IL‐8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5

“…Using a complementary approach, we treated AC with 10 mM of the GSK3β inhibitor LiCl that inhibited the phosphorylation activity of GSK3β (Supporting Information Fig. S4) and activates Wnt canonical pathway in glioblastoma‐derived cancer stem cells . In LiCl‐treated AC, c‐myc was more translocated into the nucleus (Fig.…”

“…S4) and activates Wnt canonical pathway in glioblastoma-derived cancer stem cells. 20 In LiCl-treated AC, c-myc was more translocated into the nucleus (Fig. 5a) and more bound to ABCB5 promoter (Fig.…”

“…and 100 mg/kg pemetrexed i.p. In preliminary experiments, we adopted 5 mg/kg cisplatin and 200 mg/kg pemetrexed, already used in 9 weeks old NOD‐SCID‐γ Balb/C female mice bearing patient‐derived MPM: this dosage had the same efficacy of 5 mg/kg cisplatin and 100 mg/kg pemetrexed (data not shown), but induced a 20% mortality in the chemotherapy‐treated mice between day 35 and 48. We chose the treatment with 5 mg/kg cisplatin and 100 mg/kg pemetrexed because it allowed a 100% survival until the euthanasia.…”

Mesotheliomas in Genetically Engineered Mice Unravel Mechanism of Mesothelial Carcinogenesis

“…Many of the current studies focus on target therapy to counteract the physio-pathological mechanisms allowing mesothelioma cells to grow in and invade their microenvironment, and to escape from the immune survey. For that purpose, mesotheliomas are developed in so called “mesothelioma models”, which include orthotopic or heterotopic xenografts of human mesothelioma cell lines and patient-derived xenografts in immunodeficient mice [1,2]. Moreover, experimental mesotheliomas models have been developed for different purposes.…”

Non-driver somatic alteration burden confers good prognosis in non-small cell lung cancer

“…Despite these advances in establishing the prognostic value of mutational and neoantigenic burden, their value in early-stage NSCLC cases without the treatment of immunotherapies have yet to be explored. In this study, we analyse somatic aberrations found in patient-derived xenograft (PDX) tumors that are representative of patients [19][20][21][22] , in order to evaluate the role and effect of mutation burden and neoantigen load on the prognosis of early stage completely resected NSCLC patients (Figure 1).…”