Activation of PyMT in β Cells Induces Irreversible Hyperplasia, but Oncogene-Dependent Acinar Cell Carcinomas When Activated in Pancreatic Progenitors

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.

PDX‐1

“…Re-expression of PDX-1 has been found in adult duct cells in certain conditions such as pancreatectomy and pancreatitis17, 18. PDX-1 expression also was observed in several pancreatic cancer mouse models19–21, supporting the hypothesis that PDX-1 could be participating in the carcinogenesis of pancreatic cancer in mice. Furthermore, persistent expression of PDX-1 induced acinar-to-ductal cell metaplasia in the transgenic mouse pancreas, representing a potential initiating event to malignancy22.…”

Bcl-xL promotes metastasis independent of its anti-apoptotic activity

“…For the experimental metastasis assay, either 0.5 × 10 5 MEF cells in 400 μl PBS were injected into the tail veins of male NSG mice at the age of 7–8 weeks ( n =7 CTRL group, n =8 Bcl-xL group) or 1 × 10 6 BON1-TGL cells in 100 μl PBS were injected into the left ventricle of male NSG mice at the age of 7–8 weeks ( n =5 each group), as described 52 . Mice were subjected to in vivo bioluminescent imaging using the In Vivo Imaging System Spectrum (PerkinElmer) at 0, 1, 2, 3, 5 days and 1, 2, 3, 4 weeks after tumour cells were injected, as described previously 53 .…”

Illuminating Cancer Systems with Genetically Engineered Mouse Models and Coupled Luciferase Reporters In Vivo

“…In one example, Du et al . generated a conditional tet-o-polyoma middle T antigen (PyMT)-IRES-luciferase reporter mouse, Tg( tet-o-PyMT-IRES-Luc ), to investigate the cell-specific effect of oncogene induction on the development and progression of pancreatic cancer using two previously reported conditional Tet-system mice Tg( Rip7-rtTA and Pdx1-tTA ) (78). Within 1 day of doxycycline removal, non-invasive BLI imaging allowed confirmation of subsequent oncogene withdrawal in Tg( Rip7-rtTA; tet-o-PyMT-IRES -Luc) mice.…”