Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNA-seq from human patient derived xenografts from pancreatic adenocarcinoma patients: RS10

ABSTRACT: RNA-seq from human PDX derived from radiographically resectable pancreatic adenocarcinoma patients. All surgically resected tumors were obtained after written patient consent and according to the institutional review board-approved protocols of the University of Texas M.D. Anderson Cancer Center.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Homo sapiens

SUBMITTER: Sonja Woermann

PROVIDER: E-MTAB-10116 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis.

Wörmann Sonja M SM Zhang Amy A Thege Fredrik I FI Cowan Robert W RW Rupani Dhwani N DN Wang Runsheng R Manning Sara L SL Gates Chris C Wu Weisheng W Levin-Klein Rena R Rajapakshe Kimal I KI Yu Meifang M Multani Asha S AS Kang Ya'an Y Taniguchi Cullen M CM Schlacher Katharina K Bellin Melena D MD Katz Matthew H G MHG Kim Michael P MP Fleming Jason B JB Gallinger Steven S Maddipati Ravikanth R Harris Reuben S RS Notta Faiyaz F Ross Susan R SR Maitra Anirban A Rhim Andrew D AD

Nature cancer 20211118 12

Despite efforts in understanding its underlying mechanisms, the etiology of chromosomal instability (CIN) remains unclear for many tumor types. Here, we identify CIN initiation as a previously undescribed function for APOBEC3A (A3A), a cytidine deaminase upregulated across cancer types. Using genetic mouse models of pancreatic ductal adenocarcinoma (PDA) and genomics analyses in human tumor cells we show that A3A-induced CIN leads to aggressive tumors characterized by enhanced early disseminatio ...[more]

PMID: 35121902

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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:This study, conducted by NHGRI and the M.D. Anderson Cancer Center in Houston, Texas, will develop statistical approaches for modeling family social structure and apply these models to explore the role of family social structure in participation in genetic testing and counseling, disclosure of test results and adjustment to risk status. With recent genetic advances and the ability to test for hereditary illnesses, methods that provide an understanding of the family social structure and how that structure affects the dissemination of genetic risk information are increasingly important. The data for this study were collected by the M.D. Anderson Cancer Center as part of a study on family communication and family functioning with regard to genetic testing for hereditary nonpolyposis colon cancer (HNPCC). Relatives of people with HNPCC are more likely than the general population to get colon cancer and other types of cancer if they have inherited the gene alteration (mutation) that predisposes to the disease. This alteration can be passed on from a parent to some or all of his or her children. In the M.D. Anderson Cancer Center study, telephone interviews were conducted with 80 adult members of 16 extended families with a known gene alteration predisposing for HNPCC. These participants included people who had been diagnosed with an HNPCC syndrome cancer, their unaffected family members who were at risk of carrying a gene mutation for HNPCC, and their spouses. Participants were interviewed about their feelings, moods, coping style, and relationships with their spouse, relatives, and friends, about their willingness to have genetic testing, and about their feelings and beliefs about colon cancer, cancer screening and genetic testing and counseling. Some participants were asked about their family communication style and how the family coped with the idea of genetic testing and with the results, if testing was done. The information obtained from the current study may help facilitate family participation, communication and psychological adjustment regarding risk information about genetic diseases.

Dataset Information

RNA-seq from human patient derived xenografts from pancreatic adenocarcinoma patients: RS10

Publications

APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis.

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