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    Geoffrey W. Krampitz.
    Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells are responsible for tumor development, metastasis, and recurrence, and targeting these tumor initiating cells is necessary to eradicate tumors. However, tumor initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased CD90 expression and ALDHA1 activity and provide in-vitro and in-vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in 2 cell lines and 4 primary tumors and showed that CD47, a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 co-expresses with MET and is enriched in the CD90hi cells. Furthermore, blocking CD47-SIRPα interaction promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo. This is the first in-depth profiling of PanNETs that illuminates fundamental biological processes for this class of tumors. Beginning with the index case and confirmed with additional patient tumors, we showed the dependence on paracrine signaling through the HGF/MET axis. We created a novel cell line derived from a well-differentiated PanNET tumor with autocrine HGF/MET signaling. We also identified CD90 as a marker of the tumor initiating cell population in PanNETs that allows for prospective isolation of this critical cell population. Finally, we demonstrated the efficacy of anti-CD47 therapy in PanNETs. These findings provide a foundation for developing therapeutic strategies that eliminate tumor initiating cells in PanNETs and show how deep examination of individual cases can lead to potential therapies.
    Digital Access   2017