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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

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
Show all

Summary, in 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.

Department/s

  • Division of Translational Cancer Research
  • Experimental oncology
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

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 Academy of Sciences

Topic

  • Cancer and Oncology

Status

Published

Research group

  • Experimental oncology

ISBN/ISSN/Other

  • ISSN: 1091-6490