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Project A04

Principal Investigator: Prof. Dr. Oliver Werz

Chemical mediators in the communication between monocytes/ macrophages and cancer cells, and modulation by anti-inflammatory small molecules

Structuring of cellular consortia by chemical signals is a hallmark of complex life processes. While microorganisms cooperate intensively between species, cooperation between diversely differentiated cells and tissues of the same genetic constitution is characteristic for higher organisms. If aberrantly regulated, such molecular communication is indicative or even causal for many disease states most importantly cancer. In this project we will elucidate the role of lipids as chemical mediators structuring the communication between monocytes/macrophages (Mono/Mac) and cancer cells in order to better comprehend tumor biology and to manipulate tumors by small molecules for advanced anti-cancer strategies. Complex dynamic crosstalk and interactions between proliferating cancer cells and non-malignant stromal cells create a tumor microenvironment that regulates tumor growth, progression, angiogenesis, and metastasis. In fact, non-resolving inflammation in the tumor milieu is a hallmark of cancer. Key cell populations are tumor-associated macrophages (TAMs), which derive from monocyte recruitment, infiltration and differentiation. Depending on their polarization state and functional phenotype, TAMs support tumor development by the release of non-resolving mediators or phenotypically switch into tumor-suppressive cells producing pro-resolving agents. Mono/Mac may produce a broad variety of lipid mediators (LM, belonging to the so-called metabolic lipidome), known to have pro- and anti-tumoral properties, and cancer cells exhibit aberrant LM and phospholipid (PL) profiles. However, little is known about LM and PL profiles produced by communicating macrophages and cancer cells within the tumor microenvironment, about the regulation of the metabolic lipidome at the molecular level, and how this will translate into the respective cell functionalities and tumor development. We will characterize the multifaceted communication between Mono/Mac and cancer cells via LMs and the structure of such communicating consortia, and explore how they can be manipulated by small molecules. We will investigate LM and PL patterns by employing UPLC-MS/MS-based metabololipidomics. Focus will be placed on TAM subsets M1 and M2 for which LM synthesis, in particular in direct communication with cancer cells, is essentially unknown. We aim to evaluate the specific manipulation of single, dual or multiple LM pathways, in order to redirect the synthesis of non-resolving towards pro-resolving LM and to alter the biological functions of the community.

Possible roles of lipid mediators (LM) in the communication and crosstalk between monocytes/macrophage and cancer cells. Cancer cells may educate tumor-associated macrophages towards a tumor-stimulatory phenotype (M2), and thereby repress the polarization into tumor-suppressive macrophages (M1) via LM. Inhibitory or stimulatory features of M1 and M2 on cancer cells might be conferred by LM as well. Manipulation of such communication via LM by small molecules allows influencing of tumor development.

In the long term, an increased level of understanding of chemical communication in tumor-associated inflammation might contribute to unique therapeutic opportunities. The CRC offers valuable support and knowledge by providing novel chemical mediators/secondary metabolites and new concepts how they structure microbial/plant communities. Since this project essentially deals with chemical mediators structuring the interaction of different cell types and developmental stages within a defined system it can obtain and deliver concepts of chemically-mediated interactions in consortia – even if on another level compared to the other projects of the CRC. We anticipate a truly cross-disciplinary gain in perception of multi partner interactions with a truly novel pharmacological relevance.

Team A04

Prof. Dr. Oliver Werz


Chair for Pharmaceutical / Medicinal Chemistry, Institute of Pharmacy

Friedrich Schiller University Jena

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Dr. Simona Pace


Institute of Pharmacy

Friedrich Schiller University Jena

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Dr. Andreas Koeberle


Institute of Pharmacy

Friedrich Schiller University Jena

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