Meuwissen Lab.

Meuwissen Lab.

Translational Cancer Medicine

OVERVIEW

The research themes of the Meuwissen lab focus on understanding the biology of lung cancer. Studying the molecular and cellular biology of lung cancer should provide a better insight into its onset and progression, but also lead to new molecular mechanisms for lung tumor intervention. The latter findings can then be tested in preclinical mouse models followed by translation into new clinical therapies against lung cancer.

RESEARCH INTERESTS

The research interest of the Meuwissen lab remains in the field of lung cancer. The main effort will be to study molecular mechanisms and pathways that govern the 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 in our lab:

- Role of epithelial-mesenchymal- transition in facilitating lung cancer progression and (chemo) therapy resistance

We aim our efforts at defining new regulatory mechanisms, which control epithelial-mesenchymal transition (EMT) and/or mesenchymal-epithelial transition (MET) during SCLC progression and can change the tumor’s genotype/phenotype characteristics dramatically. This, of course, has a profound effect on the tumor heterogeneity and therefore influences the outcome of most therapeutic approaches. The current emphasis is on the elucidation of some of the major molecular pathways that induce and possibly revert EMT/MET during lung tumor progression and metastases as well as influencing (chemo) therapy 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. Preliminary evidence has shown that β1 integrin signaling not only influences cellular proliferation but also onset of EMT in other solid cancers. We will proceed in characterizing molecular targets within the β1 integrin-dependent cell survival pathway. Fully mutated (knock-out, KO) candidate target genes will be engineered into our existing mouse models, which will thereby enable us to validate these molecular targets for lung tumor intervention therapy.

- Development and use of Patient-Derived Xenograft (PDX) model of human SCLC for (pre)clinical drug testing and novel immunotherapeutic approaches

We are generating sophisticated patient-derived xenotransplantation models from primary and therapy-resistant SCLC human tumors. This is technically demanding due to the 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 the recipient severely immunocompromised mice. 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.

We refine our animal models by “humanizing” severely immunocompromised mice with human hemopoietic stem cells after which these mice constitute a human adaptive immunity. Original human SCLC PDX samples will be allografted into humanized mice so that we are able to study differences in adaptive immune response against various primary human SCLCs.

Initial studies aim at the effect of variable neoantigen expression and immune checkpoint modulation on adaptive immune response efficacy against individual SCLCs. In a later stage, we plan the use of oncolytic viruses against SCLC to stimulate an increase in immune response. One of our goals is to use our advanced animal models as tools (especially for immunotherapy) in the forefront of preclinical research, so that our experiment will be ready for translational medical applications.

Ralph Meuwissen Şekil 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 that govern the onset and progression of lung cancer have been identified. 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 the 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. Currently, we established the first series of human lung cancer PDX models and we are refining them on a humanized mouse background.