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

Significance Emerging evidence suggest that the cellular composition of tumors is highly heterogeneous. Subclonal species of malignant cells may account for variability in therapeutic responses and for relapse following treatments. However, little is known about the molecular drivers of specific subsets of cancer cells. Herein, we identify expression of platelet-derived growth factor receptor beta (PDGFRβ) as a previously unrecognized feature of a minor malignant cell population in pancreatic neuroendocrine tumors. By the use of mice genetically deficient for Pdgfd, we reveal a crucial and nonredundant function for signaling by platelet-derived growth factor (PDGF)-DD in promoting functional tumor heterogeneity by providing growth-stimulatory cues. Taken together, the use of drugs targeting PDGFRβ signaling, such as the approved targeted therapy sunitinib, may affect the functional intratumoral cross talk in pancreatic neuroendocrine tumors. 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.