Metabolic crosstalk and epigenomic reprogramming of macrophages and colon cancer

In this sub-project, we aim to study the metabolic-epigenetic axis of human tumor associated macrophage (TAM) polarization in colorectal cancer (CRC), and elucidate their heterogeneity based on crosstalk with the tumor microenvironment. We use complex 3D organoid co-culture models to replicate the healthy and malignant colon environment by combining patient-derived colon epithelial or tumor cells, with matched normal or cancer associated fibroblasts, and monocyte-derived macrophages. We want to characterize fibroblast secreted factors and their impact on macrophage metabolism (with M. Schweiger, G. Schabbauer, O. Sharif) and to integrate these changes with epigenetic reprogramming. We aim to functionally characterize the spatial heterogeneity of TAMs in the organoid models and in patient samples (with T. Weichhart, A. Miller, A. Haschemi). Specific metabolites essential for epigenetic modifications (e.g SAM, KG) and microbial metabolites (together with C. Moissl-Eichinger) will be analyzed and their impact on TAM phenotype will be assessed. In order to identify immunometabolic targets in human disease, we will employ an epigenetic drug library to test for compounds, which can reprogram TAMs towards a more anti-tumorigenic immune-competent phenotype, as a potential therapeutic approach to target TAMs for treatment. Overall, our work will help to understand the metabolic and functional differences of TAM heterogeneity in CRC and provide potential targets to enhance the efficacy of current cancer therapies.

Gerda Egger

Medical University of Vienna
Department of Pathology

Ludwig Boltzmann Institute
of Applied Diagnostics

Währinger Gürtel 18-20
1090 Vienna

gerda.egger@meduniwien.ac.at
Egger Lab

Project Members

Kristina Draganic
PhD student
SFB Member

Research Publications

A systematic review on the culture methods and applications of 3D tumoroids for cancer research and personalized medicine. Kalla J, Pfneissl J, Mair T, Tran L, Egger G. Cell Oncol (Dordr). 2024 May 28. doi: 10.1007/s13402-024-00960-8. https://doi.org/10.1007/s13402-024-00960-8.

JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression. Redmer T, Raigel M, Sternberg C, Ziegler R, Probst C, Lindner D, Aufinger A, Limberger T, Trachtova K, Kodajova P, Högler S, Schlederer M, Stoiber S, Oberhuber M, Bolis M, Neubauer HA, Miranda S, Tomberger M, Harbusch NS, Garces de Los Fayos Alonso I, Sternberg F, Moriggl R, Theurillat JP, Tichy B, Bystry V, Persson JL, Mathas S, Aberger F, Strobl B, Pospisilova S, Merkel O, Egger G, Lagger S, Kenner L. Mol Cancer. 2024 May 29;23(1):114. https://doi.org/10.1186/s12943-024-02022-x.

Metabolic support by macrophages sustains colonic epithelial homeostasis. Fritsch SD, Sukhbaatar N, Gonzales K, Sahu A, Tran L, Vogel A, Mazic M, Wilson JL, Forisch S, Mayr H, Oberle R, Weiszmann J, Brenner M, Vanhoutte R, Hofmann M, Pirnes-Karhu S, Magnes C, Kühnast T, Weckwerth W, Bock C, Klavins K, Hengstschläger M, Moissl-Eichinger C, Schabbauer G, Egger G, Pirinen E, Verhelst SHL, Weichhart T. Cell Metab. 2023 Nov 7;35(11):1931-1943.e8. https://doi.org/10.1016/j.cmet.2023.09.010.

Mimicking Tumor Cell Heterogeneity of Colorectal Cancer in a Patient-derived Organoid-Fibroblast Model. Atanasova VS, de Jesus Cardona C, Hejret V, Tiefenbacher A, Mair T, Tran L, Pfneissl J, Draganić K, Binder C, Kabiljo J, Clement J, Woeran K, Neudert B, Wohlhaupter S, Haase A, Domazet S, Hengstschläger M, Mitterhauser M, Müllauer L, Tichý B, Bergmann M, Schweikert G, Hartl M, Dolznig H, Egger G. Cell Mol Gastroenterol Hepatol. 2023;15(6):1391-1419. https://doi.org/10.1016/j.jcmgh.2023.02.014.

Identification of Biomarkers and Trajectories of Prostate Cancer Progression: A Bioinformatics Fusion of Weighted Correlation Network Analysis and Machine Learning. Raheleh Sheibani-Tezerji, Carlos Uziel Pérez Malla, Gabriel Wasinger, Katarina Misura, Astrid Haase, Anna Malzer, Jessica Kalla, Loan Tran, Gerda Egger. bioRxiv 2023.03.02.530740; https://doi.org/10.1101/2023.03.02.530740.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway. Pencik J, Philippe C, Schlederer M, Atas E, Pecoraro M, Grund-Gröschke S, Li WJ, Tracz A, Heidegger I, Lagger S, Trachtová K, Oberhuber M, Heitzer E, Aksoy O, Neubauer HA, Wingelhofer B, Orlova A, Witzeneder N, Dillinger T, Redl E, Greiner G, D'Andrea D, Östman JR, Tangermann S, Hermanova I, Schäfer G, Sternberg F, Pohl EE, Sternberg C, Varady A, Horvath J, Stoiber D, Malcolm TI, Turner SD, Parkes EE, Hantusch B, Egger G, Rose-John S, Poli V, Jain S, Armstrong CWD, Hoermann G, Goffin V, Aberger F, Moriggl R, Carracedo A, McKinney C, Kennedy RD, Klocker H, Speicher MR, Tang DG, Moazzami AA, Heery DM, Hacker M, Kenner L. Mol Cancer. 2023 Aug 12;22(1):133. https://doi.org/10.1186/s12943-023-01825-8.

Zrimšek M, Kuchaříková H, Draganić K, Dobrovolná P, Heiss Spornberger V, Winkelmayer L, Hassler MR, Lochmanová G, Zdráhal Z, Egger G. Quantitative Acetylomics Uncover Acetylation-Mediated Pathway Changes Following Histone Deacetylase Inhibition in Anaplastic Large Cell Lymphoma. Cells. 2022 Aug 2;11(15):2380. https://doi.org/10.3390/cells11152380.

Dillinger T, Sheibani-Tezerji R, Pulverer W, Stelzer I, Hassler MR, Scheibelreiter J, Pérez Malla CU, Kuroll M, Domazet S, Redl E, Ely S, Brezina S, Tiefenbacher A, Rebhan K, Hübner N, Grubmüller B, Mitterhauser M, Hacker M, Weinhaeusel A, Simon J, Zeitlinger M, Gsur A, Kramer G, Shariat SF, Kenner L, Egger G. Identification of tumor tissue-derived DNA methylation biomarkers for the detection and therapy response evaluation of metastatic castration resistant prostate cancer in liquid biopsies. Mol Cancer. 2022 Jan 3;21(1):7. doi: 10.1186/s12943-021-01445-0. https://doi.org/10.1186/s12943-021-01445-0.

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis. Limberger T, Schlederer M, Trachtová K, Garces de Los Fayos Alonso I, Yang J, Högler S, Sternberg C, Bystry V, Oppelt J, Tichý B, Schmeidl M, Kodajova P, Jäger A, Neubauer HA, Oberhuber M, Schmalzbauer BS, Pospisilova S, Dolznig H, Wadsak W, Culig Z, Turner SD, Egger G, Lagger S, Kenner L. Mol Cancer. 2022 Mar 30;21(1):89. doi: 10.1186/s12943-022-01542-8. https://doi.org/10.1186/s12943-022-01542-8.

DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis. Beck MA, Fischer H, Grabner LM, Groffics T, Winter M, Tangermann S, Meischel T, Zaussinger-Haas B, Wagner P, Fischer C, Folie C, Arand J, Schöfer C, Ramsahoye B, Lagger S, Machat G, Eisenwort G, Schneider S, Podhornik A, Kothmayer M, Reichart U, Glösmann M, Tamir I, Mildner M, Sheibani-Tezerji R, Kenner L, Petzelbauer P, Egger G, Sibilia M, Ablasser A, Seiser C. EMBO J. 2021 Nov 15;40(22):e108234. https://doi.org/10.15252/embj.2021108234.