Abstract
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 β cells causes β-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, β cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded β cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and β-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 β 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.
Highlights
The pancreas is a key regulator of glucose homeostasis and of protein and carbohydrate digestion [1]
Seven tet-o-polyoma middle T antigen (PyMT)-internal ribosome entry site (IRES)-luciferase coding region (Luc) transgenic founders (#1, 2, 20, 21, 23, 29, and 39) were identified by PCR genotyping among the 39 pups obtained from the microinjection of this transgene into C57BL/6 mouse eggs, and the transgene was transmitted to the progeny of all 7 founder lines
We focused on RIP7-reverse tetracycline transactivator protein (rtTA); tet-o-PyMT-IRES-Luc bitransgenic mice derived from 2 founder lines (#21 and 29), in which the transgene was tightly regulated, as indicated by bioluminescence (Figure 1A and data not shown)
Summary
The pancreas is a key regulator of glucose homeostasis and of protein and carbohydrate digestion [1]. It is composed of two major compartments, the endocrine pancreas and the exocrine pancreas. The endocrine pancreas, which regulates metabolism and glucose homeostasis, consists of five hormone-expressing cell types – a, b, d, e, and pp cells – that produce glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide, respectively. The cellular origins of pancreatic cancers have been debated It is not clear whether different pancreatic tumor types arise from transformation of different target cells, from transformation followed by transdifferentiation, or from transformation of a common precursor, with the phenotypes determined by the differentiation effects of specific genetic alterations. Pancreatic cells have been shown to be susceptible to transdifferentiation: by ectopic expression of transcription factors in vivo, adult b cells can be transdifferentiated into a and pp cells [4], and exocrine cells can be transdifferentiated into b cells [5]
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