Pouria Jandaghi1, Hamed S Najafabadi2, Andrea S Bauer3, Andreas I Papadakis4, Matteo Fassan5, Anita Hall6, Anie Monast7, Magnus von Knebel Doeberitz8, John P Neoptolemos9, Eithne Costello9, William Greenhalf9, Aldo Scarpa10, Bence Sipos11, Daniel Auld2, Mark Lathrop2, Morag Park12, Markus W Büchler13, Oliver Strobel13, Thilo Hackert13, Nathalia A Giese13, George Zogopoulos6, Veena Sangwan14, Sidong Huang4, Yasser Riazalhosseini15, Jörg D Hoheisel3. 1. Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. 2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. 3. Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. 4. Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. 5. ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy. 6. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. 7. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. 8. Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 9. National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK. 10. ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. 11. Institute for Pathology and Neuropathology, Universitätsklinikum Tübingen, Tübingen, Germany. 12. Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montréal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. 13. Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. 14. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. 15. Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. Electronic address: Yasser.riazalhosseini@mcgill.ca.
Abstract
BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer. Copyright Â
BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer. Copyright Â
Authors: Isabel Arrillaga-Romany; Yazmin Odia; Varun V Prabhu; Rohinton S Tarapore; Krystal Merdinger; Martin Stogniew; Wolfgang Oster; Joshua E Allen; Minesh Mehta; Tracy T Batchelor; Patrick Y Wen Journal: Neuro Oncol Date: 2020-01-11 Impact factor: 12.300
Authors: Jillian S Weissenrieder; Jeffrey D Neighbors; Richard B Mailman; Raymond J Hohl Journal: J Pharmacol Exp Ther Date: 2019-04-18 Impact factor: 4.030