TY - JOUR
T1 - Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors
AU - Krampitz, Geoffrey Wayne
AU - George, Benson M.
AU - Willingham, Stephen B.
AU - Volkmer, Jens Peter
AU - Weiskopf, Kipp
AU - Jahchan, Nadine
AU - Newman, Aaron M.
AU - Sahoo, Debashis
AU - Zemek, Allison J.
AU - Yanovsky, Rebecca L.
AU - Nguyen, Julia K.
AU - Schnorr, Peter J.
AU - Mazur, Pawel K.
AU - Sage, Julien
AU - Longacre, Teri A.
AU - Visser, Brendan C.
AU - Poultsides, George A.
AU - Norton, Jeffrey A.
AU - Weissman, Irving L.
N1 - Funding Information:
This project was funded by the Virginia and D. K. Ludwig Fund for Cancer Research, an anonymous donors fund, National Cancer Institute (P01 CA139490), Siebel Stem Cell Institute and Thomas and Stacey Siebel Foundation, an A. P. Giannini Foundation Postdoctoral Research Fellowship in California, an American College of Surgeons Resident Research Scholarship, an Advanced Residency Training at Stanford (ARTS) Fellowship, and a Howard Hughes Medical Institute Medical Research Fellowship.
PY - 2016/4/19
Y1 - 2016/4/19
N2 - 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.
AB - 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.
KW - CD47
KW - CD90
KW - Cancer stem cell
KW - MET
KW - Pancreatic neuroendocrine tumor
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U2 - 10.1073/pnas.1600007113
DO - 10.1073/pnas.1600007113
M3 - Article
C2 - 27035983
AN - SCOPUS:84964394116
SN - 0027-8424
VL - 113
SP - 4464
EP - 4469
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -