title: STAT1 pathway mediates amplification of metastatic potential and resistance to therapy.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Khodarev
authors.forename: Paul
authors.initials: P
authors.lastname: Roach
authors.forename: Sean P
authors.initials: SP
authors.lastname: Pitroda
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Golden
authors.forename: Mihir
authors.initials: M
authors.lastname: Bhayani
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Shao
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: Mara G
authors.initials: MG
authors.lastname: Beveridge
authors.forename: Ravi F
authors.initials: RF
authors.lastname: Sood
authors.forename: Harold G
authors.initials: HG
authors.lastname: Sutton
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beckett
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Posner
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000818:Animals; D017209:Apoptosis; D004317:Doxorubicin / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D011839:Radiation, Ionizing; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D004317:Doxorubicin; D007371:Interferon-gamma