A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics.
- Sadanandam A 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.
- Wullschleger S Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland.
- Lyssiotis CA Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
- Grötzinger C Department of Hepatology and Gastroenterology, Charite, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
- Barbi S ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
- Bersani S ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
- Körner J Department of Hepatology and Gastroenterology, Charite, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
- Wafy I Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Lausanne (EPFL), Lausanne, Switzerland.
- Mafficini A ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
- Lawlor RT ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
- Simbolo M ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
- Asara JM Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
- Bläker H Institut für Pathologie, Charite, Campus Virchow-Klinikum, University Medicine, Berlin, Germany.
- Cantley LC Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
- Wiedenmann B Department of Hepatology and Gastroenterology, Charite, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany.
- Scarpa A 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.
- Hanahan D 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.
- 2015-10-09
Published in:
- Cancer discovery. - 2015
Animals
Biomarkers
Carbon
Cell Line, Tumor
Cell Proliferation
Cluster Analysis
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Insulin-Secreting Cells
Metabolomics
Mice
Mice, Transgenic
MicroRNAs
Mutation
Neoplasm Grading
Neoplasm Metastasis
Neoplasm Staging
Neovascularization, Pathologic
Neuroendocrine Tumors
Organogenesis
Pancreas
Pancreatic Neoplasms
RNA, Messenger
Transcriptome
English
UNLABELLED
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.
SIGNIFICANCE
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.
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.
SIGNIFICANCE
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/2159-8290.CD-15-0068
- PMID 26446169
- Persistent URL
- https://folia.unifr.ch/global/documents/102624
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