Research themes of the Meuwissen lab are focused on understanding the biology of lung cancer. Studying molecular and cellular biology of lung cancer should provide a better insight of its development and progression, but also lead to new molecular mechanisms for lung tumor intervention. The latter findings can then be tested in preclinical mouse models of lung cancer before being translated into new clinical therapies against lung cancer.RESEARCH INTERESTS
The research interest of the Meuwissen lab remains in the field of lung cancer. Main effort will be to study molecular mechanisms and pathways that govern onset, progression and maintenance of both Non-Small Cell Lung Cancer (NSCLC) as well as Small Cell Lung Cancer (SCLC). There are three central research themes that are being pursued in our project research:
- Role of epithelial-mesenchymal- transition in facilitating lung cancer (chemo)therapy resistance
Our efforts are aimed at defining a new regulatory mechanism that controls epithelial-mesenchymal transition (EMT) during SCLC progression and can cause tumor resistance against conventional chemotherapy. We make use of established human SCLC cell lines as well as at a later stage murine SCLC cell lines from our SCLC models to mimic EMT and measure its effect on chemotherapy resistance. This will be followed by the elucidation of some of the major molecular pathways that induce and possibly revert EMT during treatment leading to a change in chemotherapy response.
- New molecular targets for therapy against lung cancer We started research to elucidate the role of β1 integrin-dependent intracellular signaling on NSCLC proliferation. Somatic inactivation of β1 integrin inhibits the onset and progression of mutated Kras-driven NSCLC in our Cre/lox inducible mouse models. We will proceed in characterizing and validating molecular targets within the β1 integrin cell survival pathway for lung tumor intervention therapy. Identified new candidate target genes will be introduced in the existing models by our ability to create new inducible KO mice ourselves.
- Development and use of Patient-Derived Xenograft (PDX) model of human SCLC for (pre)clinical drug testing
We are generating sophisticated patient-derived xenotransplantation models from primary and therapy-resistant SCLC human tumors. This technically demanding (very small primary tumor size) but will enable us to have a complete human SCLC tumor panel from a sufficient number of independent patients. Primary and relapsed (therapy resistant) tumors are derived from the same individual SCLC–patient and being used to create a PDX model after transplantation into recipient severe immunocompromised mice. The complete PDX model will consist of a tumor panel obtained from 20 individual patients. Comprehensive gene expression and genomic data from the PDX tumor panel models will be performed to characterize genetic patterns shared among the different patient tumors and will in alter stage facilitate the use of this panel for genetic screens and drug efficacy testing.
Apart from above mentioned basic research efforts, we are also started to perform more translational research by generating advanced mouse models for lung cancer based on our new findings. One of our goals in the coming 5 years is to expand our pre-clinical mouse models so that they will be ready for translational medical applications.
After the initial genetic characterizations of genomic profiles from primary vs. therapy resistant SCLC, our PDX panel will allow us to perform highly relevant drug or genetic screens against both naïve primary tumors and its chemo/radiotherapy resistant relapse, finding new drugs or therapy targets.RESEARCH HIGHLIGHTS
Although the biology of lung cancer is complex, its phenotypical characteristics are very specific and well defined. In the past decades, most molecular pathways and major genetic lesions have been identified that govern onset and progression of lung cancer. In our previous work, we developed somatic mouse models that mimic both human Non-Small Cell Lung Cancer (NSCLC) as well as Small Cell Lung Cancer (SCLC). We characterized these models and made them ready for basic and applied translational research. Further analyses with our SCLC mouse models revealed a functional link between tumor cell heterogeneity and tumor progression in the form of metastasizing capacity. Active epithelial-mesenchymal transition (EMT) was shown to take place inside individual SCLC lesions and governs the extent of tumor heterogeneity. We follow up on these previous studies to investigate the molecular mechanisms of EMT in SCLC and its effect not only on tumor progression but also on acquired chemotherapy resistance. In our studies with an NSCLC model, we found that complete loss of β1 integrin could block the onset and tumor progression of KRAS-driven lung cancer. This novel finding opens a way to study how β1 integrin-dependent intracellular signaling interacts with KRAS pathway and could possibly lead to new molecular targets for therapeutic intervention.