Studies on mechanisms of interferon-gamma action in pancreatic cancer using a data-driven and model-based approach

Background: Interferon-gamma (IFN gamma) is a multifunctional cytokine with antifibrotic and antiproliferative efficiency. We previously found that pancreatic stellate cells (PSC), the main effector cells in cancer-associated fibrosis, are targets of IFNg action in the pancreas. Applying a combined experimental and computational approach, we have demonstrated a pivotal role of STAT1 in IFNg signaling in PSC. Using in vivo and in vitro models of pancreatic cancer, we have now studied IFN gamma effects on the tumor cells themselves. We hypothesize that IFNg inhibits tumor progression through two mechanisms, reduction of fibrogenesis and antiproliferative effects on the tumor cells. To elucidate the molecular action of IFN gamma, we have established a mathematical model of STAT1 activation and combined experimental studies with computer simulations. Results: In BALB/c-nu/nu mice, flank tumors composed of DSL-6A/C1 pancreatic cancer cells and PSC grew faster than pure DSL-6A/C1 cell tumors. IFN gamma inhibited the growth of both types of tumors to a similar degree. Since the stroma reaction typically reduces the efficiency of therapeutic agents, these data suggested that IFNg may retain its antitumor efficiency in PSC-containing tumors by targeting the stellate cells. Studies with cocultures of DSL-6A/C1 cells and PSC revealed a modest antiproliferative effect of IFNg under serum-free conditions. Immunoblot analysis of STAT1 phosphorylation and confocal microscopy studies on the nuclear translocation of STAT1 in DSL-6A/C1 cells suggested that IFN gamma-induced activation of the transcription factor was weaker than in PSC. The mathematical model not only reproduced the experimental data, but also underscored the conclusions drawn from the experiments by indicating that a maximum of 1/500 of total STAT1 is located as phosphorylated STAT1 in the nucleus upon IFNg treatment of the tumor cells. Conclusions: IFNg is equally effective in DSL-6A/C1 tumors with and without stellate cells. While its action in the presence of PSC may be explained by inhibition of fibrogenesis, its efficiency in PSC-free tumors is unlikely to be caused by direct effects on the tumor cells alone but may involve inhibitory effects on local stroma cells as well. To gain further insights, we also plan to apply computer simulations to the analysis of tumor growth in vivo.