Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer

Wan Chi Lin, Nirakar Rajbhandari, Chengbao Liu, Kazuhito Sakamoto, Qian Zhang, Aleata A. Triplett, Surinder Kumar Batra, Rene Opavsky, Dean W. Felsher, Dominick J DiMaio, Michael A Hollingsworth, John P. Morris IV, Matthias Hebrok, Agnieszka K. Witkiewicz, Jonathan R. Brody, Hallgeir Rui, Kay Uwe Wagner

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 reexpression 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.

Original languageEnglish (US)
Pages (from-to)1821-1830
Number of pages10
JournalCancer Research
Volume73
Issue number6
DOIs
StatePublished - Mar 15 2013

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Pancreatic Neoplasms
Adenocarcinoma
Neoplasms
Maintenance
Oncogenes
Cell Survival
Neoplastic Processes
Recurrence
Exocrine Pancreas
myc Genes
Neoplastic Stem Cells
Residual Neoplasm
Epigenomics
Up-Regulation
Neoplasm Metastasis
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lin, W. C., Rajbhandari, N., Liu, C., Sakamoto, K., Zhang, Q., Triplett, A. A., ... Wagner, K. U. (2013). Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Research, 73(6), 1821-1830. https://doi.org/10.1158/0008-5472.CAN-12-2067

Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. / Lin, Wan Chi; Rajbhandari, Nirakar; Liu, Chengbao; Sakamoto, Kazuhito; Zhang, Qian; Triplett, Aleata A.; Batra, Surinder Kumar; Opavsky, Rene; Felsher, Dean W.; DiMaio, Dominick J; Hollingsworth, Michael A; Morris IV, John P.; Hebrok, Matthias; Witkiewicz, Agnieszka K.; Brody, Jonathan R.; Rui, Hallgeir; Wagner, Kay Uwe.

In: Cancer Research, Vol. 73, No. 6, 15.03.2013, p. 1821-1830.

Research output: Contribution to journalArticle

Lin, WC, Rajbhandari, N, Liu, C, Sakamoto, K, Zhang, Q, Triplett, AA, Batra, SK, Opavsky, R, Felsher, DW, DiMaio, DJ, Hollingsworth, MA, Morris IV, JP, Hebrok, M, Witkiewicz, AK, Brody, JR, Rui, H & Wagner, KU 2013, 'Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer', Cancer Research, vol. 73, no. 6, pp. 1821-1830. https://doi.org/10.1158/0008-5472.CAN-12-2067
Lin WC, Rajbhandari N, Liu C, Sakamoto K, Zhang Q, Triplett AA et al. Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Research. 2013 Mar 15;73(6):1821-1830. https://doi.org/10.1158/0008-5472.CAN-12-2067
Lin, Wan Chi ; Rajbhandari, Nirakar ; Liu, Chengbao ; Sakamoto, Kazuhito ; Zhang, Qian ; Triplett, Aleata A. ; Batra, Surinder Kumar ; Opavsky, Rene ; Felsher, Dean W. ; DiMaio, Dominick J ; Hollingsworth, Michael A ; Morris IV, John P. ; Hebrok, Matthias ; Witkiewicz, Agnieszka K. ; Brody, Jonathan R. ; Rui, Hallgeir ; Wagner, Kay Uwe. / Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. In: Cancer Research. 2013 ; Vol. 73, No. 6. pp. 1821-1830.
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