Epigenetic reprogramming of primary pancreatic cancer cells counteracts their in vivo tumourigenicity

被引:0
|
作者
Reyhaneh Khoshchehreh
Mehdi Totonchi
Juan Carlos Ramirez
Raul Torres
Hossein Baharvand
Alexandra Aicher
Marzieh Ebrahimi
Christopher Heeschen
机构
[1] Royan Institute for Stem Cell Biology and Technology,Department of Stem Cells and Developmental Biology, Cell Science Research Center
[2] ACECR,Department of Developmental Biology
[3] University of Science and Culture,Department of Genetics, Reproductive Biomedicine Research Center
[4] Royan Institute for Reproductive Biomedicine,Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program
[5] ACECR,Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine
[6] VIVEBioTECH,Gene and Stem Cell Therapy Program
[7] Centro Nacional de Investigaciones Oncológicas (CNIO),Molecular Pathology Programme
[8] University of Barcelona,undefined
[9] Centenary Institute,undefined
[10] the University of Sydney,undefined
[11] Spanish National Cancer Research Centre (CNIO),undefined
来源
Oncogene | 2019年 / 38卷
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摘要
Pancreatic ductal adenocarcinoma (PDAC) arises through accumulation of multiple genetic alterations. However, cancer cells also acquire and depend on cancer-specific epigenetic changes. To conclusively demonstrate the crucial relevance of the epigenetic programme for the tumourigenicity of the cancer cells, we used cellular reprogramming technology to reverse these epigenetic changes. We reprogrammed human PDAC cultures using three different techniques – (1) lentivirally via induction of Yamanaka Factors (OSKM), (2) the pluripotency-associated gene OCT4 and the microRNA mir-302, or (3) using episomal vectors as a safer alternative without genomic integration. We found that induction with episomal vectors was the most efficient method to reprogram primary human PDAC cultures as well as primary human fibroblasts that served as positive controls. Successful reprogramming was evidenced by immunostaining, alkaline phosphatase staining, and real-time PCR. Intriguingly, reprogramming of primary human PDAC cultures drastically reduced their in vivo tumourigenicity, which appeared to be driven by the cells’ enhanced differentiation and loss of stemness upon transplantation. Our study demonstrates that reprogrammed primary PDAC cultures are functionally distinct from parental PDAC cells resulting in drastically reduced tumourigenicity in vitro and in vivo. Thus, epigenetic alterations account at least in part for the tumourigenicity and aggressiveness of pancreatic cancer, supporting the notion that epigenetic modulators could be a suitable approach to improve the dismal outcome of patients with pancreatic cancer.
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页码:6226 / 6239
页数:13
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