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Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

Author:
  • Eliane Cortez
  • Hanna Gladh
  • Sebastian Braun
  • Matteo Bocci
  • Eugenia Cordero
  • Niklas K Björkström
  • Hideki Miyazaki
  • Iacovos P Michael
  • Ulf Eriksson
  • Erika Folestad
  • Kristian Pietras
Publishing year: 2016
Language: English
Pages: 864-873
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 113
Issue: 7
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

Keywords

  • Cancer and Oncology

Other

Published
  • Experimental oncology
  • ISSN: 1091-6490
Kristian Pietras
E-mail: kristian.pietras [at] med.lu.se

Professor

Division of Translational Cancer Research

+46 46 222 64 29

MV404 A31B1

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Project manager

Experimental oncology