Introduction to LungSys II

Molecular processes of early tumor spread and drug resistance in lung cancer

Lung cancer is the cause of 1.37 million cancer related deaths per year. The most prevalent form of lung cancer is Non-Small Cell Lung Cancer (NSCLC). Among those adenocarcinomas of the lung arising from type II epithelial cells (pneumocytes) in bronchial alveoli are the most frequent form. The main reasons for the deadly outcome are early metastatic spread and diagnosis at an advanced stage of the disease. Metastatic spread is a multistep process characterized by enhanced motility of tumor cells and separation from the primary tumor, invasion of surrounding tissue and entry into the blood stream. The process is facilitated by multiple factors. Hepatocyte growth factor (HGF) contributes for example to the migratory behavior, transforming growth factor beta (TGFbeta) to the epithelial to mesenchymal transition (EMT) and insulin-like growth factor 1 (IGF-1R) to an increase in the expression of vascular endothelial growth factor (VEGF) that promotes the vascularization of the tumor.

Lung cancer is characterized by a particularly high mutation rate especially among smokers. Numerous driver mutations have been identified and apparently very different combinations of alterations can give rise to the disease. Many of the observed alterations affect growth factor signaling networks, and among those the most prominent example are activating mutations in the epidermal growth factor receptor (EGFR). Knowledge of these alterations opens the possibility for targeted therapy utilizing for example tyrosine kinase inhibitors or therapeutic antibodies. However, only a small subgroup of patients is eligible for targeted therapy and the majority of patients receive systemic chemotherapy. For both therapeutic options, targeted and systemic therapy, rather rapid resistance to the treatment is a major clinical problem.

Early metastatic spread and the development of drug resistance are regulated by a complex interplay between extracellular factors and intracellular alterations in tumor cells. To disentangle these highly dynamic processes the involvement of several disciplines disciplines that address the multiple scales of the topic is required. LungSys II, a CancerSys network funded by BMBF, is an interdisciplinary consortium that applies a systems biology approach to unravel mechanisms contributing to early metastatic spread in lung cancer. This is tackled by utilizing monolayer cultures, spheroid cultures and co-cultures of lung cancer cell lines. Furthermore, we perform comparative studies with patient-derived material. Of particular interest is to quantitatively link the dynamics of intracellular information processing to cellular decisions, such as cell proliferation and migration. Finally, in iterative steps these experimental models are incorporated into a mathematical multi-scale model to address the impact of cellular alterations on the tissue level. The ultimate goal is to gain insights into constellations that drive early metastatic spread and predict effective strategies for therapeutic intervention.