A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics.
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Date
2015-12ICR Author
Author
Sadanandam, A
Wullschleger, S
Lyssiotis, CA
Grötzinger, C
Barbi, S
Bersani, S
Körner, J
Wafy, I
Mafficini, A
Lawlor, RT
Simbolo, M
Asara, JM
Bläker, H
Cantley, LC
Wiedenmann, B
Scarpa, A
Hanahan, D
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Pancreas
Cell Line, Tumor
Animals
Mice, Transgenic
Humans
Mice
Neuroendocrine Tumors
Pancreatic Neoplasms
Neoplasm Metastasis
Disease Models, Animal
Neovascularization, Pathologic
Carbon
MicroRNAs
RNA, Messenger
Neoplasm Staging
Cluster Analysis
Gene Expression Profiling
Cell Proliferation
Gene Expression Regulation, Neoplastic
Organogenesis
Mutation
Insulin-Secreting Cells
Metabolomics
Neoplasm Grading
Transcriptome
Biomarkers
Research team
Systems and Precision Cancer Medicine
Language
eng
Date accepted
2015-10-05
License start date
2015-12
Citation
Cancer discovery, 2015, 5 (12), pp. 1296 - 1313