Proteotranscriptomic classification and characterization of pancreatic neuroendocrine neoplasms

Cell Rep. 2021 Oct 12;37(2):109817. doi: 10.1016/j.celrep.2021.109817.


Pancreatic neuroendocrine neoplasms (PNENs) are biologically and clinically heterogeneous. Here, we use a multi-omics approach to uncover the molecular factors underlying this heterogeneity. Transcriptomic analysis of 84 PNEN specimens, drawn from two cohorts, is substantiated with proteomic profiling and identifies four subgroups: Proliferative, PDX1-high, Alpha cell-like and Stromal/Mesenchymal. The Proliferative subgroup, consisting of both well- and poorly differentiated specimens, is associated with inferior overall survival probability. The PDX1-high and Alpha cell-like subgroups partially resemble previously described subtypes, and we further uncover distinctive metabolism-related features in the Alpha cell-like subgroup. The Stromal/Mesenchymal subgroup exhibits molecular characteristics of YAP1/WWTR1(TAZ) activation suggestive of Hippo signaling pathway involvement in PNENs. Whole-exome sequencing reveals subgroup-enriched mutational differences, supported by activity inference analysis, and identifies hypermorphic proto-oncogene variants in 14.3% of sequenced PNENs. Our study reveals differences in cellular signaling axes that provide potential directions for PNEN patient stratification and treatment strategies.

Keywords: RNA-sequencing; YAP1/TAZ; exomics; mass spectrometry; pancreatic neuroendocrine neoplasms; proteomics; transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor* / genetics
  • Biomarkers, Tumor* / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism
  • Databases, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Heterogeneity
  • Humans
  • Male
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Mutation
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / metabolism*
  • Neuroendocrine Tumors / pathology
  • Neuroendocrine Tumors / therapy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy
  • Prognosis
  • Proteome*
  • Proteomics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / genetics
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / metabolism
  • Transcriptome*
  • YAP-Signaling Proteins / genetics
  • YAP-Signaling Proteins / metabolism


  • Biomarkers, Tumor
  • Co-Repressor Proteins
  • DAXX protein, human
  • MEN1 protein, human
  • Molecular Chaperones
  • Proteome
  • Proto-Oncogene Proteins
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human