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, plateletderived 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.tumor heterogeneity | platelet-derived growth factor-DD | neuroendocrine tumor

Involvement of platelet‐derived growth factor ligands and receptors in tumorigenesis

“…A subpopulation of pancreatic neuroendocrine tumour cells in a mouse model was found to express PDGFRb, and activation of this receptor by PDGF-DD promoted tumorigenesis; similar to the case for prostate cancer discussed above, PDGF-BB had no effect [302].…”

Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D–PDGFRβ signaling

“…Thus, PDGF-D-PDGFRβ signaling by recruitment of NRP1 may actively modulate endothelial-cell-pericyte communication in temporally and spatially restricted events. Recently, we could show that PDGF-D, but not PDGF-B, promotes neuroendocrine tumor growth by activation of a subpopulation of PDGFRβ-positive tumor cells (Cortez et al, 2016). NRP1 is a good candidate to be a co-receptor for PDGF-D-induced PDGFRβ-signaling in this context, a hypothesis that waits to be investigated.…”

“…The main sites of PDGF-D expression appear to be arterial endothelial cells, but it can also be expressed in vascular smooth muscle cells and presumably other subpopulations of mural cells . PDGF-D, in contrast to PDGF-B, is dispensable for murine embryonic development , but has been shown to, for example, stimulate the proliferation of PDGFRβ-positive cells in fibrotic processes and various cancers (Andrae et al, 2008;Cortez et al, 2016;Ponten et al, 2005;Wang et al, 2010) and is associated with cardiovascular disease (Hsu and Smith, 2012). However, the biology of PDGF-D remains largely enigmatic.…”

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Preclinical and clinical studies indicate that tumor heterogeneity exists in NET. Interestingly, in a PDGF-deficient knockout mouse, a functionally important malignant cell heterogeneity could be revealed in pNET (Cortez et al 2016). Further, heterogeneity in NET is reflected by tumors with mismatch on functional imaging using FDG-PET and somatostatin receptor imaging.…”