Molekulare Analyse der tumorspezifischen Stromaaktivierung

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

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 candidate genes of activated stroma, which have an effect on cell division process, tumor cell migration and metastatic spread are validated and functionally analyzed using in vitro models. Second, disease specific signatures of activated stroma are assessed at the protein level on a large cohort of patient tissue samples. Third, with the help of new and established genetically engineered pancreatic cancer mouse models, which reflect the human situation quite well, we are able to examine the function of our candidate genes more in detail. Therefore, we further assess the applicability of murine models to evaluate the role of the activated stroma patterns in tumor progression and therapeutic interventions in the human situation. Improved diagnostic and therapeutic options for an early detection and a targeted therapy of pancreatic cancer are still essentially required.

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