Re-education of tumor promoting macrophages by RNAi based therapeutics

• Applicant: Professor Dr. Rajkumar Savai
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499344827

Lung cancer is the leading cause of cancer deaths worldwide. Emerging studies have begun to demonstrate that reprogrammed stromal cells (e.g., macrophages) play a pivotal role in tumor growth, metastasis, and resistance to therapy. With its abundant amount of existing resident stromal cells, the lung provides a unique situation for tumor stroma formation. Within the established microenvironment, tumor-associated macrophages (TAMs) are one of the most abundant and crucial non-neoplastic cell types. However, the contribution of TAMs to lung cancer has remained underexplored. We recently reported that in human lung cancer samples, tumor macrophage infiltration correlates with tumor stage and metastasis. Importantly, macrophage depletion in models of lung cancer inhibited both tumor growth and metastasis. However, a deeper understanding of molecular mechanisms underlying macrophage subpopulations and macrophage phenotypes (plasticity) that characterize lung tumor progression is essential for developing tailored therapeutic concepts focusing on macrophage reprogramming. Thus, this proposal aims to identify the miRNAs and lncRNAs deregulated in TAMs, and the significance of miRNAs and lncRNAs for TAM function, both in mouse models and humans, and the relative contributions to the lung tumor progression and metastasis in vitro and in vivo to promote TAM specific miRNA- and lncRNA- modulation as a novel therapeutic concept in lung cancer. In this respect, we will address the following specific aims: To achieve this goal, the following objectives are proposed: a) Evaluation of approaches of reeducation/reprogramming of TAMs to treat lung cancer – Role of lncRNAs. b) Evaluation of approaches of re-education/reprogramming of TAMs to treat lung cancer – Role of microRNAs. By addressing these objectives, me and my team aim to advance our scientific knowledge on how macrophages drive tumor initiation and progression and, most importantly, identify specific targets for interfering with the tumor niche’s maintenance.

• DFG Programme: Research Grants