Deciphering tumor microenvironment interactions determining lung cancer development

Lung cancer remains a high incidence and high mortality disease. The most prevalent form of Non-Small Cell Carcinoma (NSCLC) is Lung Adenocarcinoma (LUAD) followed by Squamous Cell Carcinoma (LUSC). Transforming growth factor beta (TGFβ) has a dual role in cancer as it was uncovered as a tumor suppressor but also fosters epithelial-to-mesenchymal transition (EMT) in metastatic disease. Since high levels of TGFβ have been correlated with poor outcome in lung cancer and TGFβ has been identified as a key factor contributing to remodelling of the extracellular matrix (ECM), it is of particular importance to dissect its complex role in the tumor microenvironment in lung cancer. We showed by phenotypic studies and time-resolved next generation sequencing that TGFβ induces the upregulation of the non-muscle myosin MYO10. Interestingly, our studies revealed that the expression ratio of MYO10 in the tumor and the tumor-free tissue is prognostic for overall survival of LUSC patients and facilitates the prediction of chemotherapy response (Dvornikov et al., Sci Rep 2018). However, tumor progression not only depends on alterations in the cancer cell but is much affected by the communication within the tumor microenvironment. The importance of fibroblasts in lung cancer development is underscored by the observation that patients with idiopathic lung fibrosis (IPF) have an elevated risk to develop lung cancer. In alveolar type 2 cells of an IPF mouse model that harbors a conditional knockout of the ubiquitin ligase Nedd4-2 we observed an exacerbated TGFβ-induced SMAD signal transduction and an increased expression of components associated with remodeling of the extracellular matrix (Duerr et al., Nature Commun 2020). Currently, we are developing a dynamic pathway model of TGFβ signal transduction to quantitatively assess the impact of ECM remodeling and of cell-cell communication on lung cancer cells. We explore patient derived samples to uncover mechanism-based biomarkers for early detection of lung cancer and sex-specific differences.