Development of the new multi-omics technology “OmniOmix” to harness existing clinical archives for a better understanding of cancer development

• Applicant: Francesca Tiso, Ph.D.
• Subject Area: Hematology, Oncology ; General Genetics and Functional Genome Biology ; Medical Physics, Biomedical Technology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568401464

The most effective strategy against cancer is prevention or very early interception. Both require early detection of low-stage disease, and therefore rely on identifying key molecular changes of malignant transformation and progression. Cancer is the result of the accumulation of DNA alterations impacting driver genes and leading to a cell growth advantage. It represents a multistep process during which normal cells accumulate molecular alterations, gradually acquiring malignant properties. The majority of cancer cases are diagnosed only after malignant transformation, resulting in poor survival rates and limited treatment options. A major challenge in diagnosing cancer early is our limited knowledge of its origin and initial transformations, which has hindered the identification of reliable biomarkers to detect malignancy before it is fully established. In this project, I aim to develop a new technique that enables the use of a vast but underutilized resource—archived clinical samples—to identify the key molecular changes driving cancer development. Each time a patient undergoes surgery, formaldehyde-fixed paraffin-embedded (FFPE) tissue samples are generated for diagnosis and follow-up, with any remaining tissue archived. Billions of FFPE samples are stored globally, and number grow daily. However, FFPE samples pose significant challenges for molecular analysis due to fixation-induced degradation that specifically comes into play when small amounts of material are used. My new technology “OmniOmix” will, for the first time, enable the comprehensive molecular characterization of small FFPE-derived cell clones by simultaneously extracting and analysing their epigenome, genomic DNA, transcriptome, proteome, and mitochondrial DNA. As this novel technology will allow for the analysis of limited material while also capturing multiple molecular layers, it has the potential to reveal the molecular mechanisms underlying cancer development and enable us to identify biomarkers for early detection. I will first develop OmniOmix in cell lines and subsequently validate it in a cohort of breast cancer patients carrying germline mutations in BReast CAncer Gene 1 (BRCA1). BRCA1 germline-mutated breast cancers often progress rapidly and usually lack a detectable pre-invasive cancer stage. My multi-layered FFPE-based approach will enable the reconstruction of early molecular events by analysing pure, carefully isolated cancer tissue through laser-capture microdissection (LCM). Computationally I will combine all available information to reconstruct the cancer’s evolution and identify the earliest changes that occurred in the patients. My insights will make a crucial difference for diagnosis and treatment in these women with a high risk for breast cancer. My OmniOmix approach will be applicable to different cancers and even other diseases, going beyond oncological research, and therefore push the boundaries of what is technically possible in translational genomics.

• DFG Programme: WBP Position