ID: 220: Cell-to-cell contact triggers the expression of the interferon-stimulated genes and mediates therapy resistance in cancer cell lines through a soluble factor
2015
Therapy resistance is the major hurdle in the management of cancer patients. Apart from the defects in drug uptake, therapy resistance is associated with specific gene signatures, one of them being IRDS (interferon-related DNA damage signature). Several studies demonstrated that therapy resistant tumors have abnormal activation of the genes activated in response to interferons. The mechanism triggering this signature remains to be elucidated. Using tumor cell models, we demonstrated that cell-to-cell contact is associated with the development of the gene signature similar to IRDS. The expression of interferon-stimulated genes was not dependent on STAT1, but on STAT2 and IRF9 which was alone able to drive the IRDS-like signature upon overexpression. Cells carrying increased IRDS-like signature were more resistant to chemotherapeutics than the parental sublines. Transferring conditioned media from the cells with increased expression of IRDS to freshly plated cells was able to induce the signature. We conclude that the signature was unlikely to be caused by interferons. We also gathered evidence on the involvement of JAKs into the signaling caused by a yet unrevealed cytokine. To summarize, we demonstrate that cell-to-cell contact triggers the expression of interferon-stimulated genes associated with therapy resistance. Crowding triggers secretion of a soluble factor of the non-interferon origin, which is able to induce the IRDS-like signature and promotes therapy resistance. We believe that identification a soluble factor and the mechanisms of its action are essential for pinpointing the mechanisms of therapy resistance in tumors.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
0
Citations
NaN
KQI