title: Cancer stem cell marker phenotypes are reversible and functionally homogeneous in a preclinical model of pancreatic cancer.
abstract: Survival rates associated with pancreatic cancer remain dismal despite advancements in detection and experimental treatment strategies. Genetically engineered mouse models of pancreatic tumorigenesis have gained considerable attention based on their ability to recapitulate key clinical features of human disease including chemotherapeutic resistance and fibrosis. However, it is unclear if transgenic systems exemplified by the Kras(G12D)/Trp53(R172H)/Pdx-1-Cre (KPC) mouse model recapitulate the functional heterogeneity of human pancreatic tumors harboring distinct cells with tumorigenic properties. To facilitate tracking of heterogeneous tumor cell populations, we incorporated a luciferase-based tag into the genetic background of the KPC mouse model. We isolated pancreatic cancer cells from multiple independent tumor lines and found that roughly 1 out of 87 cells exhibited tumorigenic capability. Notably, this frequency is significantly higher than reported for human pancreatic adenocarcinomas. Cancer stem cell (CSC) markers, including CD133, CD24, Sca-1, and functional Aldefluor activity, were unable to discriminate tumorigenic from nontumorigenic cells in syngeneic transplants. Furthermore, three-dimensional spheroid cultures originating from KPC tumors did not enrich for cells with stem-like characteristics and were not significantly more tumorigenic than cells cultured as monolayers. Additionally, we did not observe significant differences in response to gemcitabine or salinomycin in several isolated subpopulations. Taken together, these studies show that the hierarchical organization of CSCs in human disease is not recapitulated in a commonly used mouse model of pancreatic cancer and therefore provide a new view of the phenotypic and functional heterogeneity of tumor cells.
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Dosch
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Ziemke
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Amrith
authors.initials: A
authors.lastname: Shettigar
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan. jssl@med.umich.edu.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Sebolt-Leopold
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D051927:CD24 Antigen / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011714:Pyrans / Q000494:pharmacology; D018874:Spheroids, Cellular; D013194:Staining and Labeling; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000093542:Gemcitabine; D000095662:Polyether Polyketides
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000950:Antigens, Ly; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D003841:Deoxycytidine; D006023:Glycoproteins; D008156:Luciferases; D008565:Membrane Proteins; D010455:Peptides; D016283:Proto-Oncogene Proteins p21(ras); D011714:Pyrans; D016159:Tumor Suppressor Protein p53; D000093542:Gemcitabine; C497890:Cd24a protein, mouse; C074650:Ly6a protein, mouse; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse; C010327:salinomycin; D000095662:Polyether Polyketides