RTG 2338 Targets in Toxicology
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P11 - Environmental mutational imprints of lung adenocarcinoma

Lung adenocarcinoma (LADC) is the deadliest cancer worldwide and is caused by environmental physicochemical carcinogens such as tobacco smoke and radiation. The cell lineages, the mode of mutation accumulation, and the molecular pathways that lead to LADC have not been defined, since genetic mouse models do not recapitulate the complex mutation spectrum of human LADC identified by human molecular fingerprinting studies. We recently achieved induction of LADC in mice and derivation of cell lines thereof using environmental carcinogens such as tobacco chemicals, tobacco smoke, and γ-radiation and are in the process of characterizing these tumors at the morphological, cellular, and molecular levels. We also combined molecular and epidemiologic data to develop molecular risk prediction tools for LADC in four human patient cohorts. Using these breakthroughs, we have defined that different environmental inciting agents imprint unique molecular signatures in LADC and are at the verge of discovering novel carcinogen-mutation relationships and of identifying the cellular descent of these tumors. We also pinned unknown oncogene addiction partners and produced novel molecular risk prediction tools that can predict LADC molecular class risk by smoking/radiation exposure. Here we aim to: i) define the molecular imprints of tobacco smoke and radiation in LADC; ii) detect the pulmonary cellular lineages targeted by each carcinogen; iii) map tobacco smoke and radiation molecular signatures in human LADC; and iv) identify novel mutation addiction partners as new therapeutic targets against LADC.This work is positioned to revolutionize current thinking about LADC, one of the heaviest permutated human cancers, to identify unknown LADC drivers, and to aid in the development of new therapies aimed at drugging unknown addiction partners of LADC oncogenes.

Dr. Georgios Stathopoulos, MD PhD

CPC Helmholtz Zentrum München