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Pancreatic Neuroendocrine Tumors

Jurisdiction:

China

Organ System:

Pancreas

Funding Organizations:

  • National Key Research and Development Program of China
  • National Natural Science Foundation of China
  • Strategic Priority Research Program of the Chinese Academy of Sciences
  • Shanghai Leading Talent Program of Eastern Talent Plan
  • Sailing Project of Science and Technology Commission of Shanghai Municipality
  • China Postdoctoral Science Foundation
  • Shanghai Municipal Science and Technology Major Project
  • Scientific Innovation Project of Shanghai Education Committee
  • Baidu Foundation of China
  • Clinical Research Plan Shanghai Hospital Development Center
  • Science Foundation of Peking University Cancer Hospital
  • CAS project for young scientists in basic research
  • Xuhui District Intelligence Medical Hospital Cooperation Project

Research Organizations:

  • Fudan University, China
  • Peking University Cancer Hospital & Institute, China
  • Chinese Academy of Sciences, China

Principal Investigators:

  • Xianjun Yu
  • Jianmin Wu
  • Hu Zhou
  • Gang Jin
  • Daming Gao

Publication:

External Links:

The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, and clinicopathological features. Drug screening using patient-derived tumor organoids identifies cyclin-dependent kinase (CDK) 5 and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D) as ubiquitous and subtype-specific targets, respectively, with in vivo validation using xenograft models. Together, our proteogenomic analyses illustrate a comprehensive molecular landscape of NF-PanNETs, revealing biological insights and therapeutic vulnerabilities.

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