title: A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics.
abstract: Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation-enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities.
  
  
  CONCLUSIONS
  This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy.
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland. Division of Molecular Pathology, Institute of Cancer Research (ICR), London, United Kingdom. anguraj.sadanandam@icr.ac.uk douglas.hanahan@epfl.ch aldo.scarpa@univr.it.
authors.forename: Anguraj
authors.initials: A
authors.lastname: Sadanandam
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wullschleger
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Department of Hepatology and Gastroenterology, Charite, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grötzinger
authors.affiliation: ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Barbi
authors.affiliation: ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Bersani
authors.affiliation: Department of Hepatology and Gastroenterology, Charite, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Körner
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Ismael
authors.initials: I
authors.lastname: Wafy
authors.affiliation: ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mafficini
authors.affiliation: ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.affiliation: ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simbolo
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Institut für Pathologie, Charite, Campus Virchow-Klinikum, University Medicine, Berlin, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bläker
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Hepatology and Gastroenterology, Charite, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.affiliation: ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. anguraj.sadanandam@icr.ac.uk douglas.hanahan@epfl.ch aldo.scarpa@univr.it.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland. anguraj.sadanandam@icr.ac.uk douglas.hanahan@epfl.ch aldo.scarpa@univr.it.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D000818:Animals; D015415:Biomarkers; D002244:Carbon / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D055432:Metabolomics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics; D010179:Pancreas / Q000196:embryology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger; D002244:Carbon