title: Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors.
abstract: 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, 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 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 CD90(hi)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.
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; krampitz@stanford.edu irv@stanford.edu.
authors.forename: Geoffrey Wayne
authors.initials: GW
authors.lastname: Krampitz
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Benson M
authors.initials: BM
authors.lastname: George
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Willingham
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Volkmer
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Nadine
authors.initials: N
authors.lastname: Jahchan
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Newman
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Zemek
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Yanovsky
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Julia K
authors.initials: JK
authors.lastname: Nguyen
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schnorr
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Visser
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: George A
authors.initials: GA
authors.lastname: Poultsides
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Norton
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 krampitz@stanford.edu irv@stanford.edu.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D051928:CD47 Antigen / Q000276:immunology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000276:immunology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000276:immunology; D018358:Neuroendocrine Tumors / Q000276:immunology / Q000473:pathology / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000090063:Proto-Oncogene Mas; D050697:Retinal Dehydrogenase / Q000276:immunology; D018800:Thy-1 Antigens / Q000276:immunology; D019139:Tumor Escape; D023041:Xenograft Model Antitumor Assays
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D007527:Isoenzymes; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D018800:Thy-1 Antigens; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase
keywords: CD47; CD90; MET; cancer stem cell; pancreatic neuroendocrine tumor