STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to TherapyReport as inadecuate

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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 STAT1H genotype are selected by the lung microenvironment. STAT1H tumor cells also demonstrate resistance to IFN-gamma IFNγ, ionizing radiation IR, and doxorubicin relative to parental B16F1 and low expressors of the IFN-STAT1 pathway STAT1L genotype. Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress.


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.

Author: Nikolai N. Khodarev , Paul Roach , Sean P. Pitroda, Daniel W. Golden, Mihir Bhayani, Michael Y. Shao, Thomas E. Darga, Mara G. Be



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