A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2015-12-01
Date Accepted
2015-10-05
Abstract
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.
Citation
Cancer discovery, 2015, 5 (12), pp. 1296 - 1313
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
Collections
Research Team
Systems and Precision Cancer Medicine