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Genomic profiling of patient-derived xenografts identify high level “passenger” gene aberrations associated with better prognosis in non-small cell lung cancer

ABSTRACT: Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers and to evaluate novel therapeutics, as they reflect clinical cancers more closely than established tumor cell lines. With >100 PDXs established from resected non-small cell lung carcinomas (NSCLC), we reported previously that xenograftability correlates significantly with poorer patient prognosis. In this study, genomic, transcriptomic, and proteomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with cell lines, using publicly available data on the latter. A higher number of somatic alterations among 865 frequently altered genes in the PDX tumors was associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by a lower number of alterations; this was validated with the TCGA lung cancer patient dataset (HR=0.28, p=0.000022). These passenger-like alterations, identified in PDXs, link cell-cell signaling and adhesion to patient prognosis.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE68929 | GEO | 2016/10/26

SECONDARY ACCESSION(S): PRJNA284129

REPOSITORIES: GEO

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Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.

Project description:Background: In high-grade serous ovarian cancer (HGSOC) intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations, but frequent epigenetic alterations including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated. Aims of this study were to explore how representative HGSOC PDXs are for their corresponding patient tumors methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods: Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450K. Further, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the predictive/prognostic value of the identified genes. Results: Only 0.6-1.0% of all analyzed CpGs (388,696 CpGs) changed significantly (p<0.01) during propagation showing that HGSOC PDXs are epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6% of CpG sites in comparison to untreated PDXs (p<0.01, FDR<10%). Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g. Src family kinase pathway). Particularly, C-terminal Src kinase (CSK) gene was successfully validated for epigenetic regulation in different PDX models and ovarian cancer cell lines. Low CSK methylation and high CSK expression were both significantly associated (p<0.05) with improved progression free survival and overall survival in HGSOC patients. Conclusion: HGSOC PDXs resemble the global epigenome of patients over many generations, which can be modulated by epigenetic drugs. Novel epigenetically regulated genes such as CSK and related pathways were identified in HGSOC. Our results encourage future application of PDXs for cancer epigenome studies.

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Genomic profiling of patient-derived xenografts identify high level “passenger” gene aberrations associated with better prognosis in non-small cell lung cancer

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