Integrative approach to uncover oncogenic mechanisms of DICER1-associated cancers.

• Applicant: Dr. Felix Kommoss
• Subject Area: Pathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523898075

DICER1 syndrome is a genetic disorder, caused by germline DICER1 alterations, that predisposes patients to develop rare tumors in various organs. Ten years after the discovery of recurrent missense mutations as the second hit in the tumors from susceptible individuals, there has been little progress in the path from genomic discovery towards treatments. This failure of translation is likely due to the absence of genetically and pathologically true model systems required for such research. Researchers have recently developed a transgenic murine model that conditionally activates DICER1 mutations in cross tissue mesenchymal progenitor cells, which leads to the development of renal tumors. Histological assessment revealed that these murine tumors resemble tumor types seen in individuals with DICER1 syndrome. However, more data is needed to ascertain that these murine Dicer1 tumors recapitulate their human counterparts at the molecular level across the spectrum of human DICER1-associated neoplasms. Herein, I propose to determine whether the murine Dicer1 tumor model represents human DICER1 syndrome-associated neoplasms molecularly and to identify oncogenic features of DICER1 syndrome-associated cancers using whole proteome profiling for future therapeutic development. To achieve this objective, I propose to perform methylomic and genomic analyses on murine renal HDT tumors and compare them to previously generated profiles of various subtypes of DICER1-associated cancers (Kommoss et al, manuscript in review). The results will help clarify if these murine Dicer1 tumors recapitulate their human counterparts at the molecular level and represent an adequate disease model to study the spectrum of human DICER1-associated neoplasms. Furthermore, I propose to perform mass spectrometry to determine proteomic profiles of murine renal tumors, their proposed cell of origin (Hic+ kidney mesenchymal cells) and human DICER1 syndrome-associated cancers to identify oncogenic pathways driving tumor development and progression. The proposed project will allow me to develop skills in state-of-the-art methods in a world-class environment to understand mechanistic underpinnings of clinically apparent genetic cancer syndromes. The herein generated comprehensive molecular characterization of human and murine DICER1-associated cancers will allow future investigations into candidate therapeutic targets, thereby laying the ground for continued studies upon my return to Germany.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Dr. David Huntsman