title: Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden;
authors.forename: Eliane
authors.initials: E
authors.lastname: Cortez
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden;
authors.forename: Hanna
authors.initials: H
authors.lastname: Gladh
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Braun
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden;
authors.forename: Matteo
authors.initials: M
authors.lastname: Bocci
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden;
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cordero
authors.affiliation: Department of Medicine, Karolinska Institutet, SE-14186, Stockholm, Sweden;
authors.forename: Niklas K
authors.initials: NK
authors.lastname: Björkström
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden;
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyazaki
authors.affiliation: Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Iacovos P
authors.initials: IP
authors.lastname: Michael
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden;
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden;
authors.forename: Erika
authors.initials: E
authors.lastname: Folestad
authors.affiliation: Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden; kristian.pietras@med.lu.se.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D009389:Neovascularization, Pathologic; D018358:Neuroendocrine Tumors / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*
chemical_list: D008222:Lymphokines; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor
keywords: neuroendocrine tumor; platelet-derived growth factor-DD; tumor heterogeneity
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