Identification of molecular mechanisms underlying lung cancer metastasis

• Applicant: Michela Serresi, Ph.D.
• Subject Area: Pathology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428550787

Metastasis is the endpoint of tumorigenesis and is usually diagnosed in an untreatable stage. The molecular mechanisms underlying metastases and biomarkers for early intervention are largely unknown. In our current application, we proposed to identify such mechanisms and biomarkers in rodent models for aggressive lung adenocarcinoma. Our main objective is to faithfully recapitulate the gradual process that occurs during tumor progression starting from the formation of the primary tumor to the intravasation in the bloodstream up to the extravasation and the final colonization of the new metastatic station. We combined dedicated animal models and the systematic dissection of the metastatic process by genetic screens in vitro and in vivo thereby developing unique datasets and skills. Specifically, we first generated and characterized an orthotopic model for systematic dissection of the metastatic process in lung cancer and then performed two independent in vivo GOF (gain-of-function) screens in a mouse host and one genome-wide GOF (gain-of-function) screen in a rat host. Deep sequencing identified nine candidate genes potentially driving tumor progression and metastasis, which are currently being validated in vitro and in vivo. Among other striking observations, both GOF screens in the mouse pointed to mild KRAS transcriptional amplification as a driver of primary tumor growth and metastasis. The validation of eight additional candidate oncogenes besides KRAS is currently ongoing in immunocompetent mouse models for lung cancer. Herewith, we request the continuation of the DFG support to finalize this work program through the following aims: • Finalizing the KRAS functional validation to gain insights into the mechanisms through which KRAS amplification promotes lung tumor growth and metastasis formation. •Validating eight metastatic candidate drivers in vivo and - if time permits - gathering evidence on their mechanism of action.• Expanding our strategy for genome-scale screening, building on the pilot genome-wide screen performed as a part of previous project.

• DFG Programme: Research Grants