Hamid Kashkar - B 4

The role of mitochondrial apoptosis in macrophages and macrophage-derived tumor-promoting inflammation

Abstract

Macrophages are the major regulators of inflammation, coordinate tissue homeostasis/repair and provide the forefront of innate immune defense. These fundamental functions can be manipulated by a number of non-autonomous insults resulting in a causal association of macrophages with diseases such as cancer. Indeed, macrophages represent the major components of tumor microenvironment and the analysis of their function has led to the dissection of tumor-promoting inflammation. It is increasingly evident that macrophage-derived inflammation can be modulated through macrophage-apoptosis either by limiting macrophage life-span or by interfering with intracellular inflammatory signaling. However, how this dynamic process is regulated and coordinates tissue inflammation is not yet completely understood. Here we aim to decipher the role of the mitochondrial apoptotic pathway in macrophage life span and macrophage-derived tissue inflammation in cancer. Unique opportunities will arise from the study of novel conditional Bcl2 knock-in mouse (inhibiting mitochondrial apoptosis) enabling us to block mitochondrial apoptosis selectively in myeloid compartment and the use of small molecules BH3 mimetic (ABT-199) and SMAC mimetic (birinapant) (promoting apoptosis) currently used in clinical trial for cancer patients. These analyses will provide the first evidence about how macrophage stress responses to systemic anti-cancer treatment may coordinate tumor associated inflammatory environment and impact on cancer progression.

Clinical/medical relevance and sustainability in disease understanding

Accumulating evidence suggest that anti-cancer cytotoxic treatment modalities profoundly influence tumor associated macrophages (TAMs) and their anti-tumor activity grossly depends on the crosstalk between malignant cells and macrophages. Thus, the knowledge of how mitochondrial apoptosis controls macrophage function will be substantial to understand macrophage-derived tumor-promoting inflammatory mechanisms and will pave the way for innovative macrophage-centered diagnostic and therapeutic strategies.


Prof. Dr. rer. nat. Hamid Kashkar

Inst. for Med. Microbiology, Immunology & Hygiene

Prof. Dr. rer. nat. Hamid Kashkar

Principal Investigator B 4

h.kashkar@uni-koeln.de

Work +49 221 478 84091

Institute for Medical Microbiology, Immunology and Hygiene (IMMIH)
Goldenfelsstraße 19-21
50935 Cologne

http://immih.uk-koeln.de/forschung/ag-kashkar

Publications - Hamid Kashkar

Link to PubMed