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Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer.
|Title||Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Lin W-C, Rajbhandari N, Liu C, Sakamoto K, Zhang Q, Triplett AA, Batra SK, Opavsky R, Felsher DW, Dimaio DJ, Hollingsworth MA, Morris JP, Hebrok M, Witkiewicz AK, Brody JR, Rui H, Wagner K-U|
|Date Published||2013 Mar 15|
The initiation and progression of pancreatic ductal adenocarcinoma (PDAC) is governed by a series of genetic and epigenetic changes, but it is still unknown whether these alterations are required for the maintenance of primary and metastatic PDAC. We show here that the c-Myc oncogene is upregulated throughout the entire process of neoplastic progression in human PDAC and in genetically engineered mice that express mutant Kras. To experimentally address whether c-Myc is essential for the growth and survival of cancer cells, we developed a novel mouse model that allows a temporally and spatially controlled expression of this oncogene in pancreatic progenitors and derived lineages of the exocrine pancreas. Unlike previous reports, upregulation of c-Myc was sufficient to induce the formation of adenocarcinomas after a short latency without additional genetic manipulation of cell survival pathways. Deficiency in Cdkn2a increased the rate of metastasis but had no effect on tumor latency or c-Myc-mediated cancer maintenance. Despite a macroscopically complete regression of primary, metastatic, and transplantable tumors following the ablation of c-Myc, some cancer cells remained dormant. A significant number of these residual neoplastic cells expressed cancer stem cell markers, and re-expression of exogenous c-Myc in these cells led to rapid cancer recurrence. Collectively, the results of this study suggest that c-Myc plays a significant role in the progression and maintenance of PDAC, but besides targeting this oncogene or its downstream effectors, additional therapeutic strategies are necessary to eradicate residual cancer cells to prevent disease recurrence.
|Alternate Journal||Cancer Res.|