Activation of PyMT in beta cells induces irreversible hyperplasia, but oncogene-dependent acinar cell carcinomas when activated in pancreatic progenitors.
It is unclear whether the cellular origin of various forms of pancreatic cancer involves transformation or transdifferentiation of different target cells or whether tumors arise from common precursors, with tumor types determined by the specific genetic alterations. Previous studies suggested that pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells. To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we generated transgenic mice that carry tetracycline-inducible PyMT and a linked luciferase reporter. Induction of PyMT in beta cells causes beta-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, beta cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded beta cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and beta-cell hyperplasia. The survival of acinar tumor cells is dependent on continued expression of PyMT. Our findings indicate that PyMT can induce exocrine tumors from pancreatic progenitor cells, but cells in the beta cell lineage are not transdifferentiated toward exocrine cell types by PyMT; instead, they undergo oncogene-dependent hyperplastic growth, but do not require PyMT for survival.
Du
Yi-Chieh Nancy
YC
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. duy@mskcc.org
Klimstra
David S
DS
Varmus
Harold
H
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D018267:Carcinoma, Acinar Cell / Q000378:metabolism*; D002454:Cell Differentiation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D017930:Genes, Reporter; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D010179:Pancreas / Q000378:metabolism*; D010641:Phenotype; D013752:Tetracycline / Q000494:pharmacology
D000952:Antigens, Polyomavirus Transforming; D008156:Luciferases; D013752:Tetracycline