Molekulare Analyse der tumorspezifischen Stromaaktivierung

Coordinator:		PD Dr. Jörg Kleeff
Institution:		Chirurgische Klinik und Poliklinik, Technische Universität München
Homepage:		www.pankreasforschung.de

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with cancer cells alone comprising less than one fifth of the tumor mass. PDAC is also extremely resistant to conventional as well as targeted therapeutic options. In the last decade, pancreatic stellate cells (PSC) have been identified as the principal source of this abundant extracellular matrix (ECM) that infiltrates and envelops the normal parenchyma as well as tumor cells. The activated stroma can modulate and even initiate tumorigenesis. Moreover, malignant and non-malignant components of the tumor mass can exert a variety of effects on each other that alter angiogenesis, ECM components, epithelial-mesenchymal interactions, substratum adhesiveness, and cancer directed immune responses, all of which influence tumor behavior.
In this regard, this subproject aims to fulfill three main objectives: First, already identified disease specific profiles of activated stroma will be validated using in vitro three dimensional culture of PSC and cancer cells. Second, disease specific signatures of activated stroma will be assessed at the mRNA and protein level on a large cohort of patient sera and tissue samples. Upon refinement of the identified profiles/candiate genes, genetically engineered mouse models will be used to assess the applicability of murine models to evaluate the role of the activated stroma patterns detected in humans as a diagnostic as well as a therapeutic option. By substracting the differentially expressed genes of the activated stroma from the bulk tissue data, it is possible reduce the background noise to refine targets specific for cancer.