Massimiliano Mazzone

The research began to explore vascular biology, uncovering a novel endothelial cell phenotype during hypoxic tissue perfusion (Mazzone et al., Cell, 2009; Leite de Oliveira et al., Cancer Cell, 2012; Ehling et al., Circulation Res, 2019). This pivotal discovery propelled investigations into how inflammatory cells respond to hypoxia, with the goal of restoring blood flow in conditions such as cancer and ischemia (Rolny et al., Cancer Cell, 2011; Casazza et al., Cancer Cell, 2013; Takeda et al., Nature, 2011; Hamm et al., EMBO Mol Med, 2013).

Concurrently, the research’s work highlighted the adaptive mechanisms of cancer cells under glucose or oxygen deprivation, elucidating how they remodel their metabolic and oxygen-sensing machinery to evade cell death (Di Conza et al., Cell Rep, 2017a; Di Conza et al., Cell Rep, 2017b). Pioneering the understanding of tumor-associated macrophages (TAMs), the research group established the critical role played by TAM localization and metabolism in shaping their pro-tumoral, angiogenic, and immunosuppressive traits (Casazza et al., Cancer Cell, 2013; Bieniasz-Krzywiec et al., Cell Metabolism, 2019; Wenes et al., Cell Metabolism, 2016; Palmieri et al., Cell Rep, 2017; Menga et al., EMBO Mol Med, 2020; Menga et al., EMBO Rep, 2021).

Then, the research activity extended beyond cancer, encompassing immune cell responses in diverse contexts such as inflammation, infections, and tissue regeneration, significantly advancing the understanding of vessel remodeling, macrophage diversity, immune suppression, T cell exclusion, and resistance to immunotherapy (Celus et al., Cancer Immunol Res, 2021; Cappellesso et al., Nature Cancer, 2022; Pinioti et al., Cancer Immunol Res, 2023). The impactful translational outcomes of their work were evident in ongoing clinical trials, the establishment of two spin-off companies, numerous industrial collaborations, drug screening initiatives, a licensed diagnostic kit, and an immunotherapeutic antibody, highlighting and supporting the practical application and commercialization of their research in the realms of healthcare and therapeutics.

1. Cappellesso F, Orban M-P, Shirgaonkar N, Berardi E, Serneels J, Neveu M-A, di Molfetta D, Piccapane F, Caroppo R, Debellis L, Ostyn T, Joudiou N, Mignion L, Richiardone E, Jordan B.F., Gallez B, Corbet C, Roskams T, Dasgupta R, Tejpar S, Di Matteo M, Taverna D, Reshkin S.J., Topal B, Virga F, Mazzone M. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. Nature Cancer, 3(12) :1464-1483 (2022).
2. Bieniasz-Krzywiec P, Martín-Pérez R, Ehling M, Kroes R, Aldeni C, García-Caballero M, Prenen H, Noel A, Smeet A, Floris G, Van Ginderachter JA, and Mazzone M. Podoplanin-expressing macrophages are required for lymphangiogenesis and lymphatic metastasis in breast cancer. Cell Metabolism, 30 (5):917-947 (2019).
3. Shang M, Cappellesso F, Amorim R, Serneels J, Virga F, Di Matteo M, Eelen G, Carobbio S, Rincon MY, De Bock K, Maechler P, Ho PC, Sandri M, Ghesquière B, Carmeliet P, Berardi E, and Mazzone M. Macrophage-derived glutamine boosts satellite cells and muscle regeneration. Nature, 587(7835):626-631 (2020).
4. Finisguerra V, Di Conza G, Di Matteo M, Serneels J, Costa S, Thompson R, Wauters E, Walmsley S, Prenen H, Granot Z, Casazza A, and Mazzone M. MET is required for the recruitement of anti-tumoural neutrophils. Nature, 522(7556): 349-353 (2015).
5. Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, and Mazzone M. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores anti-tumor immunity. Cancer Cell, 24(6): 695-709 (2013).