The inflammatory micromilieu: decisive role in tumor plasticity in pancreatic cancer

• Applicant: Professor Dr. Matthias Gaida
• Subject Area: Pathology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321664872

Pancreatic ductal adenocarcinoma is one of the deadliest solid malignancies. Typically, an infiltrate of immune cells is apparent consisting mainly of T cells, neutrophils, and macrophages. High T cell infiltrates are generally associated with a better prognosis. However, in our recent work we identified in pancreatic tumors a tumor promoting T cell type with characteristics of Th17-cells that produced – among others - interleukin 21 (IL-21). Concomitantly, the IL-21 receptor was expressed on pancreatic tumor cells, and its expression was associated with aggressive disease. Moreover, we could link infiltrated neutrophil granulocytes to promote tumor invasion and change the microarchitecture of established cancers. As downstream target, the transcription factor Blimp-1 was identified in the tumor cells, and first data showed a link between Blimp-1 expression and functional alterations of the tumor cells. In direct follow-up of these findings the present proposal has two specific aims: (1) the tumor promoting capacity of Th17-like cells and neutrophils will be analyzed by advanced histological methods with focus on alterations of the tumor microarchitecture and induction of an invasive tumor cell phenotype. Moreover, underlying molecular alterations, particularly related to Blimp-1, will be assessed in in vitro and in vivo models, with special emphasis on tumor cell invasion and adhesion. As ultimate goal, the predictive value of those molecules regarding outcome and cancer progression will be evaluated, as well as their potential role as targets for an immune-intervention. (2) Invasion of pancreatic tumor cells into the neighboring fatty tissue will be studied. Although general tumor invasion mechanisms are well characterized, it is not known whether similar molecular mechanisms are operative in fatty tissue. Hence, we plan to study the invasive front with advanced histomorphological and immunohistological methods with focus on the phenotypical analysis of the invading tumor cells. These studies will be completed by in vitro and in vivo assays. The obtained data will give evidence on the participation of fatty tissue derived mediators in the invasivity of pancreatic cancer.

• DFG Programme: Research Grants