title: Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer.
abstract: 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.
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198-5950, USA.
authors: Wan-chi
authors: WC
authors: Lin
authors: Nirakar
authors: N
authors: Rajbhandari
authors: Chengbao
authors: C
authors: Liu
authors: Kazuhito
authors: K
authors: Sakamoto
authors: Qian
authors: Q
authors: Zhang
authors: Aleata A
authors: AA
authors: Triplett
authors: Surinder K
authors: SK
authors: Batra
authors: Rene
authors: R
authors: Opavsky
authors: Dean W
authors: DW
authors: Felsher
authors: Dominick J
authors: DJ
authors: DiMaio
authors: Michael A
authors: MA
authors: Hollingsworth
authors: John P
authors: JP
authors: Morris
authors: Matthias
authors: M
authors: Hebrok
authors: Agnieszka K
authors: AK
authors: Witkiewicz
authors: Jonathan R
authors: JR
authors: Brody
authors: Hallgeir
authors: H
authors: Rui
authors: Kay-Uwe
authors: KU
authors: Wagner
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016259:Genes, myc; D019942:Genes, p16; D051379:Mice; D009364:Neoplasm Recurrence, Local; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*