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RP 9

Dr. María Gómez-Serrano: the EVITA project 

Extracellular VesIcles from Tumor-associated Adipocytes: characterization of their functional role in the ovarian cancer microenvironment


Maria Gomez-Serrano

Ovarian cancer (OC) is a deadly disease largely due to relapse associated with chemotherapy resistance and immune evasion. A hallmark of OC is its tumor microenvironment (TME), which is unique among all cancer entities. It is composed of anatomically and functionally different compartments, i.e., the solid tumor masses with the invaded surrounding host tissues (most notably the omentum) and the peritoneal fluid, which frequently occurs as ascites at advanced stages. While the most prominent host cells in OC ascites are tumor-associated macrophages and T cells, the major cell types in the metastasized omentum are adipocytes, mesothelial cells and fibroblasts. Despite the crucial role of these cell types for tumor progression, their functional communication remains largely obscure. Recently, the communication via extracellular vesicles (EVs) emerged as an important mechanism in cellular crosstalk. EVs are released by all cell types and allow the encapsulated transfer of molecules (i.e. proteins, RNAs and lipids), altering the function and the phenotype of the recipient cell. Ascites from OC patients contain substantial amounts of EVs originating from both tumor and tumor-associated host cells, such as cancer-associated adipocytes (CAAs). It has been shown that these EVs possess tumor-promoting and immune suppressive properties.

Project overview

Maria Gomez-Serrano

A crucial role of EV trafficking in the TME is well known, especially regarding host cell reprogramming through molecule transfer from tumor cells. However, although the omentum is thought to promote OC metastasis, little is known about the role adipocytes exert on tumor cells. The aim of our project is to contribute to a better understanding of adipocyte-derived EVs (Ad-EVs) in OC with a particular focus on p53 and NF-kB signaling pathways. We hypothesize that Ad-EVs are altered under CAA reprogramming, impinge on malignant cells and thereby contribute to cancer progression and drug resistance, which is sustained by recent studies. However, the Ad-EV cargo remains largely unknown, which is surprising given the importance of the omentum in OC. For these reasons, the characterization of molecular signatures of EVs released by tumor-associated adipocytes and the evaluation of their biological function in OC progression and chemoresistance constitutes the main focus of our research. Relapse, immune evasion and drug resistance are recurrent features in OC, which highlights a clinical need for novel treatment strategies. Understanding the intercellular crosstalk and the contribution of specific EV-cell types into the OC secretome is a promising approach in this direction.

Highlighted References

Malandrino, M. I. et al. Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid induced triglyceride accumulation and inflammation. Am J Physiol Endocrinol Metab 308, E756-769,doi:10.1152/ajpendo.00362.2014 (2015).

Gomez-Serrano, M. et al. Proteome-wide alterations on adipose tissue from obese patients as age-, diabetes- and gender-specific hallmarks. Sci Rep 6, 25756, doi:10.1038/srep25756 (2016).

Marinaro, F. et al. Unraveling the Molecular Signature of Extracellular Vesicles From Endometrial-Derived Mesenchymal Stem Cells: Potential Modulatory Effects and Therapeutic Applications. Front Bioeng Biotechnol 7, 431, doi:10.3389/fbioe.2019.00431 (2019).

Lopez, E. et al. The Immunomodulatory Signature of Extracellular Vesicles From Cardiosphere-Derived Cells: A Proteomic and miRNA Profiling. Front Cell Dev Biol 8, 321, doi:10.3389/fcell.2020.00321 (2020).

Dietze, R. et al. Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions with implications for ovarian cancer. Theranostics; 11(3):1377-1395, doi:10.7150/thno.52442 (2021).

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