STAT1 pathway mediates amplification of metastatic potential and resistance to therapy

PLoS One. 2009 Jun 8;4(6):e5821. doi: 10.1371/journal.pone.0005821.


Background: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress.

Methodology/principal findings: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress.

Conclusions: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Doxorubicin / pharmacology
  • Interferon-gamma / metabolism
  • Lung / metabolism
  • Melanoma, Experimental / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Phenotype
  • Radiation, Ionizing
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcription, Genetic


  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Doxorubicin
  • Interferon-gamma