Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 16; pp. 4464 - 4469
• Main Authors: Krampitz, Geoffrey Wayne, George, Benson M., Willingham, Stephen B., Volkmer, Jens-Peter, Weiskopf, Kipp, Jahchan, Nadine, Newman, Aaron M., Sahoo, Debashis, Zemek, Allison J., Yanovsky, Rebecca L., Nguyen, Julia K., Schnorr, Peter J., Mazur, Pawel K., Sage, Julien, Longacre, Teri A., Visser, Brendan C., Poultsides, George A., Norton, Jeffrey A., Weissman, Irving L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.04.2016; National Acad Sciences
• Subjects: Animals; Biological Sciences; CD47 Antigen - immunology; Cells; Endocrine system; Female; Humans; Isoenzymes - immunology; Male; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Neoplasm Proteins - immunology; Neuroendocrine Tumors - immunology; Neuroendocrine Tumors - pathology; Neuroendocrine Tumors - therapy; Pancreas; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Pathogenesis; Retinal Dehydrogenase - immunology; Thy-1 Antigens - immunology; Tumor Escape; Tumors; Xenograft Model Antitumor Assays; CD47; cancer stem cell; MET; pancreatic neuroendocrine tumor; CD90
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1600007113

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 is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumorinitiating 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 proto-oncogene 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 cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a “don’t eat me” signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90hi cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo.