Targeting mechanisms underlying poor-prognosis high neutrophil-to-lymphocyte ratio metastatic colorectal cancer

• Applicant: Dr. Rene-Filip Jackstadt
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539308505

Metastatic colorectal cancer (mCRC) ranks among the highest cancer related death in the world (globally 1.1 million predicted deaths), hence better understanding of mCRC and improved clinically intervention strategies are urgently needed. Disease progression and poor prognosis of CRC is often linked to systemic inflammation. Compelling evidence has accumulated that specifically high neutrophil-to-lymphocyte ratio (NLR) in circulation are useful to identify patients with poor-outcome. This NLR triggered by tumor induced systemic inflammation may be involved in the creation of immunosuppressive environment in the pre-metastatic niche. However, current knowledge about the functional role of systemic inflammation in CRC metastasis is limited, and underlying mechanisms are unknown. Based on our preliminary data we hypothesize that epithelial Notch1-signalling, a strong driver of metastasis, controls the expression of CXCL12 in primary tumors that causes systemic inflammation by release of CXCR4-positive neutrophils from bone marrow. This systemic inflammation driven high NLR may facilitate metastasis and represents a pharmacological actionable target. The aim of this project is to functionally characterize the cellular and molecular mechanisms of systemic inflammation controlled by the Notch1-CXCL12-CXCR4 axis and unravel the importance of this process for metastasis in order to develop novel therapeutic strategies based on the easily detectable NLR. This will be achieved by utilizing different immunocompetent state-of-the-art mouse models and fresh or archival patient materials. Therapeutic potential will be assessed by pharmacological targeting of the Notch1-CXCL12-CXCR4 axis to decode the function of immunosuppressive neutrophils in combinatorial treatments with immune-checkpoint inhibition in mouse models of poor-prognosis CRC and high NLR. Together, this work program will allow combining an easily applicable prognostic strategy with a tailored therapy to extend patients lifespan mCRC.

• DFG Programme: Research Grants