Unknown,Transcriptomics,Genomics,Proteomics

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Genomic profiling of patient-derived xenografts identify high level âpassengerâ 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. Total RNAs from xenograftswere amplified by DASL kit and hybridized to Illumina HT12v4 chip

ORGANISM(S): Mus musculus

SUBMITTER: Ming Tsao

PROVIDER: E-GEOD-68929 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors.

Wang Dennis D Pham Nhu-An NA Tong Jiefei J Sakashita Shingo S Allo Ghassan G Kim Lucia L Yanagawa Naoki N Raghavan Vibha V Wei Yuhong Y To Christine C Trinh Quang M QM Starmans Maud H W MH Chan-Seng-Yue Michelle A MA Chadwick Dianne D Li Lei L Zhu Chang-Qi CQ Liu Ni N Li Ming M Lee Sharon S Ignatchenko Vladimir V Strumpf Dan D Taylor Paul P Moghal Nadeem N Liu Geoffrey G Boutros Paul C PC Kislinger Thomas T Pintilie Melania M Jurisica Igor I Shepherd Frances A FA McPherson John D JD Muthuswamy Lakshmi L Moran Michael F MF Tsao Ming-Sound MS

International journal of cancer 20161107 3

Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficie ...[more]

PMID: 27750381

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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.

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

Publications

Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors.

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Dataset Information

Genomic profiling of patient-derived xenografts identify high level âpassengerâ gene aberrations associated with better prognosis in non-small cell lung cancer

Publications

Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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