The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

eLife

Christopher VE Wright¹  Spencer G Willet¹  Fong Chen Pan¹  Gabriela M Cash²  Jean-Paul De La O²  Nathan M Krah²  L Charles Murtaugh²  Chinh Q Hoang³  Galvin H Swift³  Raymond J MacDonald³  Mary P Bronner⁴ 

[1] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States;Department of Human Genetics, University of Utah, Salt Lake City, United States;Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States;Department of Pathology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, United States;

关键词: pancreatic cancer;    differentiation;    pancreatitis;   

DOI  :  10.7554/eLife.07125

来源: DOAJ

【 摘 要 】

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

【 授权许可】

Unknown