Biology subjects

Bardeesy, N.

Publications and source records attributed to Bardeesy, N..

2 recordsLinked to original sources

bioRxiv2020

Nuclear GSK-3β and Oncogenic KRas Promote Expansion of Terminal Duct Cells and the Development of Intraductal Papillary Mucinous Neoplasm

Intraductal papillary mucinous neoplasm (IPMN) represents one type of pancreatic ductal adenocarcinoma (PDA) precursor lesion, however its cell-of-origin remains unclear. Here we describe a new mouse model in which pancreas-specific Cre activation of a nuclear glycogen synthase kinase-3{beta} transgene is combined with oncogenic KRas (referred to as KNGC). KNGC mice show accumulation of neoplastic ductal cells at 4-weeks that progressively develop into IPMN with low-grade dysplasia in advanced age. RNA-sequencing identified expression of several terminal duct cell lineage genes including Agr2 and Aqp5. Interestingly, Aqp5, a water channel, was found to be required for the development of IPMN lesions in KNGC mice. Staining of human IPMN samples indicates that these preneoplastic lesions also arise from expansion of the terminal duct population. Altogether, these data highlight the utility of the KNGC model for understanding the biology of IPMN and potential utility in defining predictive biomarkers of IPMN - PDA development. Statement of significanceUnderstanding the cell-of-origin of IPMN is crucial to developing early detection methods that specifically target aggressive precursors of PDA. This work, using a novel mouse model, identifies Aqp5-modulated development of Agr2+ terminal ducts that could potentially serve as a clinical biomarker for IPMN.

cancer biology↗

bioRxiv2020

ISL2 is an epigenetically silenced tumor suppressor and regulator of metabolism in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Uncovering mechanisms responsible for the heterogeneous clinical features of this disease is an essential step toward developing improved and more specific therapeutic approaches. Here, we sought to identify transcriptional regulators of aggressive PDAC growth through in vivo CRISPR screening of epigenetic and transcription factors in an orthotopic model. We identified the ISL LIM homeobox 2 (ISL2) gene as a tumor suppressor whose depletion enhances the proliferation of human PDAC cells in vitro and in vivo and cooperates with activated KRAS to initiate PDAC in a murine model. Conversely, the upregulation of ISL2 expression through CRISPR-mediated locus-specific epigenetic editing results in reduced cell proliferation. Importantly, ISL2 is epigenetically silenced through DNA methylation in ~60% of PDAC tumors, which correlates with poor patient outcome. Functional studies showed that ISL2 loss rewires metabolic gene expression, and consequently potentiates oxidative phosphorylation while reducing glycolysis. This metabolic shift creates selective vulnerability to small molecule inhibitors of mitochondrial respiration and fatty acid oxidation. Collectively, these findings reveal ISL2 as a novel tumor suppressor whose inactivation drives metabolic reprogramming in an aggressive PDAC subset and point to potential therapeutic vulnerabilities in these tumors.

molecular biology↗