Targeting chemotherapy induced metabolic escape mechanisms to reduce cancer metastasis

• Applicant: Nicole Kiweler, Ph.D.
• Subject Area: Hematology, Oncology ; Biochemistry ; Public Health, Healthcare Research, Social and Occupational Medicine ; Cell Biology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 447238381

Cancer is a major health burden in Europe and worldwide. While significant progress has been made in recent decades to treat primary tumors, metastatic cancer is still associated with devastatingly low survival rates. Enhanced understanding of the basic disease mechanisms and the according improvement of clinical treatment is the most promising approach to conquer this unmet clinical need. Intriguingly, it is meanwhile anticipated that certain chemotherapeutic regimens promote metastasis. As genetic mutations could not be identified as sole drivers of metastasis, alternative cellular adaptation mechanisms such as posttranslational modifications (PTMs) of proteins are discussed. Building blocks for such PTMs originate from cellular metabolism. In fact, metabolic alterations pose one of the most sensitive and immediate cellular responses to chemotherapy. Thus, metabolism is intricately linked to PTMs and metastasis. Consequently, a comprehensive analysis considering all these aspects, as intended in this project, is required to monitor the full cascade from chemotherapy to metastasis. Specifically, this project investigates chemotherapy induced alterations of the central metabolic building block acetyl-CoA and their relevance for protein acetylation and subsequent pro-metastatic signalling. This holistic approach will identify and validate novel pharmacologic intervention points to prevent metastatic tumor escape mechanisms upon chemotherapy. To obtain the required quantitative data, the project employs and extends available stable isotope-assisted in vitro and in vivo flux analysis tools and additional Omics approaches to link metabolic alterations to PTMs in the context of metastasis. This project sets an excellent training framework by combining individual aspects of the metastatic cascade with state-of-the-art experimental techniques.

• DFG Programme: WBP Fellowship
• International Connection: Luxembourg
• Host: Dr. Johannes Meiser