Lineage specific NEDD9 signaling
Studies of the cancer genome helped characterizing specific tumor drivers and allowed the development of tailored targeted therapies in oncology. However, the immense plasticity and heterogeneity of malignant tumors still remains a major challenge in cancer treatment as it results in insufficient therapeutic activity and the rapid development of resistance, due to compensatory regulations in the complex oncogenic signaling network. The rational combination of targeted therapeutics is forward-looking to overcome these obstacles and targeting proteins, which serve as signaling nodes in the rewired signaling cascades might have a particular potential to contribute to this strategy.
NEDD9 (also: enhancer of filamentation 1 (HEF1) or CAS-L) has been recognized as a highly connected node in cellular signaling networks, serving as a protein scaffold for a significant number of interaction partners. The adaptor protein plays a major role in transducing signals from cell surface receptors - most notably integrins - and cytoplasmic protein tyrosine kinases, such as SRC and Aurora kinase A (AURKA). Thereby it modulates a number of key cellular functions involved in tumor growth and metastasis including cell cycle control, migration, invasion and cilia dynamics. NEDD9 overexpression is frequent and drives tumor progression in a number of entities, in particular adenocarcinomas, such as of the lung and breast, but also in neural crest-derived tumors, such as malignant melanoma. In these entities NEDD9, not “drugable” itself, has been shown to significantly impact responsiveness to targeted therapies. Namely, in adenocarcinomas NEDD9 confers to drug resistance against tyrosine kinase inhibitors, including those targeting AURKA and SRC. Moreover in neuroblastoma cells NEDD9 mediates responsiveness to retinoids, an important substance group for neuroblastoma treatment.
In our project we aim to systematically analyze NEDD9-dependent gene- and protein expression in adenocarcinomas and neural crest-derived tumors to identify lineage-specific signaling-dependencies of NEDD9. With a multidisciplinary approach we will utilize different tumor models, namely murine models both in vivo and ex vivo as well as human cancer cell lines to combine the resulting expression data in an integrative cross-species analysis. Our overall goal is to identify lineage-specific signaling-dependencies of NEDD9 to provide novel potential targets for tailored treatment of genetically defined cancer patients and to improve the overall understanding of both NEDD9 function and cancer diversity.