STAT1 pathway mediates amplification of metastatic potential and resistance to therapy.
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.
Khodarev
Nikolai N
NN
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois, United States of America.
Roach
Paul
P
Pitroda
Sean P
SP
Golden
Daniel W
DW
Bhayani
Mihir
M
Shao
Michael Y
MY
Darga
Thomas E
TE
Beveridge
Mara G
MG
Sood
Ravi F
RF
Sutton
Harold G
HG
Beckett
Michael A
MA
Mauceri
Helena J
HJ
Posner
Mitchell C
MC
Weichselbaum
Ralph R
RR
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
D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D004317:Doxorubicin; D007371:Interferon-gamma