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 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.