Project ID CM-HD2024_68


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Tissue Macrophage Ageing and Cancer

Age is the biggest risk factor for cancer with more than half of cases diagnosed in people over the age of 60. Ageing is associated with a heightened inflammatory state called – Inflammageing – that is likely related to the aetiology of age-related diseases. Paradoxically, ageing is also associated with suppression of the adaptive immune system. The combination of increased inflammation and immune suppression is a hallmark of cancer and the mechanisms underpinning this dichotomy in the aged immune system are likely to play important roles in disease progression and response to therapy.
Tumour-associated macrophages (TAMs) are strongly linked with cancer progression both in humans and animal models, but the impact of ageing on macrophages and their roles in cancer remains unknown. We hypothesise that are-related changes in macrophage homeostasis and function are linked to cancer progression and these may represent tractable points for intervention in cancer therapy. This project will address four major research questions: 1) How does ageing affect macrophage development and homeostasis? 2) How does ageing and macrophage longevity impact progression of cancer? 3) What are the intrinsic pathways that control macrophage homeostasis and cancer progression? 4) What extrinsic factors affect macrophage function during ageing and contribute to cancer progression? The outcomes of this project will include; 1) a comprehensive proteogenomic analysis of tissue macrophages during ageing and tumorigenesis, 2) the identification of intrinsic and extrinsic factors that affect macrophage function in aged tissues and impact cancer progression and 3) the evaluation of the impact of ageing on macrophages and clinical outcomes in cancer patients.
This project will employ state-of-the-art proteogenomic techniques, including single cell RNA sequencing, spectral flow cytometry, spatial transcriptomics and imaging mass cytometry. The majority of experiments will be performed in mouse models, with key observations confirmed in human cell culture models and clinical samples.

Representative Publications

Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer. Etzerodt A, Moulin M, Doktor TK, Delfini M, Mossadegh-Keller N, Bajenoff M, Sieweke MH, Moestrup SK, Auphan-Anezin N, Lawrence T. J Exp Med. 2020. doi: 10.1084/jem.20191869. Specific targeting of CD163(+) TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression. Etzerodt A, Tsalkitzi K, Maniecki M, Damsky W, Delfini M, Baudoin E, Moulin M, Bosenberg M, Graversen JH, Auphan-Anezin N, Moestrup SK, Lawrence T. J Exp Med. 2019. doi: 10.1084/jem.20182124. Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression. Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, Ulas T, Papantonopoulou O, Van Eck M, Auphan-Anezin N, Bebien M, Verthuy C, Vu Manh TP, Turner M, Dalod M, Schultze JL, Lawrence T. Cell Metabolism. 2019. doi: 10.1016/j.cmet.2019.02.016.
Prolidase inactivation in obesity determines the severity of fibro-inflammation and metabolic disturbances. V Pellegrinelli, S Rodriguez Cuenca, C Rouault, G Bidault, S Virtue, H Schilbert, JM Moreno-Navarret, MC Vázquez Borrego, B. Pucker, R Dias, M Dale, M. Campbell, S Carobbio, J Aron-Wisnewsky, M.Vacca, M. Den Hoed, R Loos, S Mukhopadhyay, JM Fernández-Real, K Clément, A. Vidal-Puig. Nature Metabolism,2022 Apr,4(4):476-494. DOI: 10.1038/s42255-022-00561-5 Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer. Michela Masetti, Roberta Carriero, Federica Portale, Bianca Partini, Marco Erreni, Andrea Ponzetta, Elena Magrini, Giulia Marelli, Nicolò Morina, Piergiuseppe Colombo, David Waugh, Federico Colombo, Haan JMM den Joke, Clelia Peano, Paolo Kunderfranco, Massimo Lazzeri, Giorgio Guazzoni, Enrico Lugli, Jolanda Brummelman, , Ronald DePinho, Siamon Gordon, Subhankar Mukhopadhyay Diletta Di Mitri. The Journal of experimental medicine,2022 Feb,7,219(2), doi: 10.1084/jem.20210564. Loss of IL-10 signalling in macrophages limits bacterial killing driven by PGE2. Subhankar Mukhopadhyay, Eva Heinz, Kaur Alasoo, Immacolata Porreca, Amy Yeung, Tobias Schwerd, Jessica Forbester, Christine Hale, Chukwuma Agu, Yoonha Choi, Julia Rodrigues David Thomas, Daniel Gaffney, William C Skarne, Nicholas Thomson Holm Uhlig, Gordon Dougan and Fiona Powrie. Journal of Experimental Medicine, 2020 Feb 3;217(2). doi: 10.1084/jem.20180649.