Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers

Cell Rep. 2017 Feb 28;18(9):2243-2255. doi: 10.1016/j.celrep.2017.02.013.

Abstract

Mutant KRAS and c-MYC are oncogenic drivers and rational therapeutic targets for the treatment of pancreatic cancer. Although tumor growth and homeostasis are largely dependent on these oncogenes, a few residual cancer cells are able to survive the ablation of mutant KRAS and c-MYC. By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, we have identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. The pharmacological inhibition of IGF-1R reduces residual disease burden and cancer recurrence, suggesting that this molecular pathway is crucial for the survival of cancer cells in the absence of the primary oncogenic drivers.

Keywords: AKT; IGF1 signaling; KRAS; c-MYC; cancer dormancy; genetic engineering; mouse models; oncogenes; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autocrine Communication / genetics*
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression / genetics
  • Genes, myc / genetics
  • Humans
  • Insulin-Like Growth Factor I / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation / genetics
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Oncogenes / genetics*
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Receptor, IGF Type 1 / genetics
  • Signal Transduction / genetics*

Substances

  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras)