Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors

• DOI: 10.1073/pnas.1600007113
• Publication Date: 2016-04-01T04:16:50Z
• Authors: Geoffrey Wayne Kr...; Benson M. George; Stephen B. Willin...; Jens-Peter Volkmer; Kipp Weiskopf; Nadine Jahchan; Aaron M. Newman; Debashis Sahoo; Allison J. Zemek; Rebecca L. Yanovsky; Julia K. Nguyen; Peter J. Schnorr; Pawel K. Mazur; Julien Sage; Teri A. Longacre; Brendan C. Visser; George A. Poultsides; Jeffrey A. Norton; Irving L. Weissman
• Keywords: Male; cancer stem cell; Immunology; Oncology and Carcinogenesis; CD47 Antigen; Mice, SCID; SCID; pancreatic neuroendocrine tumor; Proto-Oncogene Mas; Aldehyde Dehydrogenase 1 Family; Pancreatic Cancer; Mice; Rare Diseases; Clinical Research; Mice, Inbred NOD; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Neoplasm Metastasis; CD47; Cancer; Biomedical and Clinical Sciences; Retinal Dehydrogenase; Biological Sciences; Stem Cell Research; Xenograft Model Antitumor Assays; Neoplasm Proteins; 3. Good health; CD90; Isoenzymes; Pancreatic Neoplasms; Neuroendocrine Tumors; MET; Inbred NOD; Thy-1 Antigens; Female; Tumor Escape; Biochemistry and Cell Biology; Digestive Diseases; Biotechnology

Significance This is the first in-depth profiling of pancreatic neuroendocrine tumors (PanNETs), to our knowledge, 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 hepatocyte growth factor (HGF)/receptor tyrosine kinase MET axis. We created a novel cell line derived from a well-differentiated PanNET with autocrine HGF/MET signaling. We also identified the cell-surface protein 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.