Gruppo Chiarugi
Tumor metabolism and microenvironment Lab
Coordinator
Paola Chiarugi
Brief Biographical sketch of the Coordinator
Paola Chiarugi is Full Professor of Biochemistry of the Faculty of Medicine and Surgery at the University of Florence and was Director of the Department of Experimental and Clinical Biomedical Sciences in 2016-2020 period. She studied Biology (MSc) at University of Florence and graduated in 1989.
She coordinated and coauthored several studies on plasticity of motility in cancer cells, as epithelial mesenchymal transition or mesenchymal amoeboid transition motility and their anoikis resistance. She studied tumor microenvironment and cancer metabolic deregulation for more than 15 years, particularly focusing on fibroblasts, macrophages and endothelial cells. At present, she coordinates the Tumor Metabolism and Microenvironment group of the Department of Experimental and Clinic Biomedical Sciences in Florence and she is the PI of the Metabolomics Unit funded in 2016.
She is member of the Evaluation Boards of the Breakthrough Breast Cancer Research Unit, University of Manchester and of the Institute Marie Curie, Paris.
Member of the Scientific Board the Doctorate/Phd Program in
PhD in Biochemistry and Molecular Biology
Member of the following Scientific Societies
Italian Society of Biochemistry and Molecular Biology, Italian Society of Cancerology, European Association for Cancer Research
Member of editorial board of the following Journals
Editor for FEBS Journal, FEBS OpenBIO, Journal of Molecular Medicine,
Research Team
Current research interest
Our laboratory aims to characterize these metabolic changes in cancer and stromal cell populations and understand how they alter the tumor progression in vitro and in vivo, with a particular focus on intratumoral lactate within prostate cancers.
Metabolic landscape of the tumor microenvironment: role of lactate
In the last years we have reported that tumor-stroma metabolic interactions sustain progression and metastasis of PCa. We reported that lactate produced by cancer-associated fibroblasts (CAFs) is rapidly uploaded by PCa cancer cells via the monocarboxylate transporter 1 (MCT1), a process that drives the activity of the NAD+-dependent deacetylase Sirtuin1 and the subsequent activation of PGC-1α. The uploaded lactate drives PCa cells towards a real metabolic reprogramming and acquisition of cancer aggressive features, including de novo achievement of stemness traits and enhanced invasiveness and metastatic potential. We reported that lactate-dependent metabolic rewiring, e.g. lactate-derived metabolic Krebs cycle intermediates, leads to alterations of tumor-stroma epigenetics, thereby affecting cancer cell behavior. Indeed, lactate upload leads to Krebs cycle fueling leading to three metabolic consequences, both of them very strategic for PCa progression.
After lactate upload we reported a citrate-depended de novo lipid synthesis and accumulation into lipid droplets, serving upon request as reservoir for acetyl moieties for histone acetylation and epigenetic rewiring of motility and survival to stress. Third, the unbalanced ratio between alpha-ketoglutarate and succinate/fumarate, due to lactate fueling of Krebs cycle, leads to inhibition of histone demethylases, thereby affecting histone methylation pattern and PCa cell migration and extracellular matrix remodeling. Hence during PCa progression environmental lactate plays pivotal roles for metastatic dissemination, mainly affecting motility, survival and stemness of cancer cells through metabolic and epigenetic rewiring via acetylation and methylation of histones. These findings have of course underscored several key pharmacological targets showing high impact on PCa progression, as MCT1 lactate transporter, citrate lyase (ACLY), histone acetylation readers as BRD4 and histone methylases WDR5. We are now interested in dissecting the role of Lactylation driven by lactate, either affecting histones and non-histone proteins during Pca progression.
Metabolic-dependent ferroptosis resistance as a novel potential target to prevent prostate cancer metastatic dissemination
Metastatic dissemination is a critical and inefficient step of cancer progression, as disseminating cancer cells (DCCs) are exposed to severe oxidative stress in the bloodstream, making them highly vulnerable to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, a subset of DCCs acquires resistance to ferroptosis, thereby gaining a selective advantage for successful metastasis. This project aims to elucidate the metabolic mechanisms underlying ferroptosis resistance in DCCs, with a particular focus on the role of lactate and aspartate-driven metabolic pathways. By identifying key metabolic adaptations that sustain redox homeostasis and prevent lipid peroxidation, the study seeks to uncover novel metabolic vulnerabilities that can be therapeutically targeted to limit metastatic dissemination.
Gender difference in metabolism and immunity in melanoma
Female melanoma patients generally exhibit significantly longer survival and better disease progression than male patients. Generally, altered metabolism in cancer cells may create metabolically imbalanced, challenging microenvironment, resulting in an enrichment of immunesuppressive metabolites (lactate). As negative correlations between LDHA expression (i.e. lactate secretion) and T cell activation has been revealed in human melanoma patients and hormonal context may explain sex-related anti-melanoma immune response, the project will allow i) to identify a gender influence on both the metabolic and immune profile of melanoma and ii) to define central hubs in the metabolic/signaling signature that can be targeted, in order to design a combined targeting approach to improve efficacy of standard immunetherapies in melanoma
Targeting metabolic dysregulation to bypass immune escape in human colorectal carcinoma
Cololorectal cancer (CRC) is a highly heterogeneous disease categorized into four consensus molecular subtypes (CMS) with different biological and immunological features. Among these,CMS1 is characterized by high microsatellite instability, immune activation and responsiveness to immune checkpoint inhibitors (ICIs). In contrast, CMS3 displays metabolic dysregulation and resistance to immunotherapy. Emerging evidence suggests that metabolic rewiring can profoundly influence the tumour microenvironment (TME) and contribute to tumor immune-escape. This project aims to investigate how lipid metabolism reprogramming in CMS3 colorectal cancer contributes to elude immune surveillance and to assess whether targeting specific metabolic pathways, particularly involved in the synthesis of arachidonic acid-derived bioactive lipid mediators, may restore an immune-prone CMS1-like phenotype, providing a rationale for novel combinatorial therapeutic strategies.
Key words
Tumor metabolic deregulation, prostate cancer, tumor microenvironment, lactate, lipid droplets,
Current/recent sources of funding
PRIN 2017-2021 to Paola Chiarugi
PNRR Ecosistemi della Ricerca to Paola Chiarugi
AIRC IG 2021-2026 to Paola Chiarugi
PNR 2021-2027 to Paola Chiarugi
PNRR CN3 to Elisa Giannoni
Gender Medicine 2021-2022 – to Elisa Giannoni
PRIN 2022 to Elisa Giannoni,
PRIN 2022 PNRR to Elisa Giannoni
Fondazione Berlucchi to Luigi Ippolito
5 best pubblications
Iozzo, M., Pardella, E., Giannoni, E., Chiarugi, P. The role of protein lactylation: A kaleidoscopic post-translational modification in cancer, Molecular Cell, 2025, 85(7), pp. 1263–1279
Pranzini E, Ippolito L, Pardella E, Giannoni E, Chiarugi P. Adapt and shape: metabolic features within the metastatic niche. Trends Endocrinol Metab. 2025 Mar;36(3):205-218.
Ippolito L, Duatti A, Iozzo M, Comito G, Pardella E, Lorito N, Bacci M, Pranzini E, Santi A, Sandrini G, Catapano CV, Serni S, Spatafora P, Morandi A, Giannoni E, Chiarugi P. Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer. EMBO Rep. 2024 Aug;25(8):3506-3531.
Ippolito L, Comito G, Parri M, Iozzo M, Duatti A, Virgilio F, Lorito N, Bacci M, Pardella E, Sandrini G, Bianchini F, Damiano R, Ferrone L, la Marca G, Serni S, Spatafora P, Catapano CV, Morandi A, Giannoni E, Chiarugi P. Lactate Rewires Lipid Metabolism and Sustains a Metabolic-Epigenetic Axis in Prostate Cancer. Cancer Res. 2022 Apr 1;82(7):1267-1282.
Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, Lanciotti M, Serni S, Cirri P, Chiarugi P. Cancer Res. 2012 Oct 1;72(19):5130-40.
Previous research experiences
Paola Chiarugi has studied for up to 10 years the structure-function relationship of tyrosine phosphatases. Her studies contributed to the elucidation of the mechanism of action of these enzymes with mutagenesis techniques and then to the definition of their role in the control of cell proliferation, adhesion and motility. More recently her interests move toward the redox regulation of oxidant-sensitive proteins during cell proliferation and cell adhesion to extracellular matrix, particularly focusing on the role of tyrosine phosphorylation on chemo-attractant and chemo-repulsive receptor signalling and during anchorage dependent and independent growth. More recently, her scientific activity is focused on deregulation of tumor metabolism and energetics, as well as on cancer microenvironment, including effects of cancer associated fibroblasts, macrophages and lymphocytes.
Main scientific contributions
Paola Chiarugi gained the following main tasks:
She studied the role of a pro-oxidant environment in cancer progression, contributing studies on different cell motility styles, focusing on both mesenchymal and amoeboid motility and their advantages in different tumor microenvironment conditions, stress response to oxidants, to acidity or to hypoxia, as well the role of small GTPases for these features. She studied the epigenetic transitions leading to these phenotypes, i.e. epithelial mesenchymal transition (EMT) and mesenchymal amoeboid transition (MAT), contributing several papers. Top 2 papers are:
- Giannoni E, et al, Redox regulation of anoikis resistance of metastatic prostate cancer cells: key role for Src and EGFR-mediated pro-survival signals. Oncogene. 2009 May 21;28(20):2074-86.
- Parri M, et al., EphA2 re-expression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res. 2009 Mar1;69(5):2072-81
- She investigated the relationship between cancer cells and their stromal counterpart, obtained by aggressive prostate cancer bearing patients. These studies have been focused on cancer associated fibroblasts, macrophages or lymphocytes and produced several publications, indicating that these accessory cell populations promote epithelial mesenchymal transition, achievement of stem traits, anoikis resistance and immune modulation, thereby strongly affecting tumor progression. Top 2 papers on these studies are:
- Giannoni E, Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010 Sep 1;70(17):6945-56.
- Comito G,et al., Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene. 2019 May;38(19):3681-3695.
- She investigated the metabolic deregulation within tumor:stroma interplay. In prostate cancer models, she identified a metabolic reciprocal loop, mediated by delivery of lactate by CAFs, uploaded by OXPHOS-addicted cancer cells, regulating their malignancy. This tumor:stroma lactate-mediated interaction, sustains metabolic adaptation of malignant prostate cancer cells towards OXPHOS and lipid metabolism, as well as non-cell-autonomous adaptive resistance to cancer targeted therapies and immune modulation. Top studies on these topics are:
- Fiaschi T, et al., Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumorstroma interplay. Cancer Res. 2012, 72(19):5130-40.
- Comito G, Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene. 2019 Jan 21. doi: 10.1038/s41388-019-0688-7.
- Apicella, M., Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. Cell Metab. 2018 Dec 4;28(6):848-865.e6.
- Chen J, et al. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat Genet. 2018 Feb;50(2):219-228.
- Ippolito, l., et al., Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene. 2019 Jul;38(27):5339-5355.
- She drives the Metabolomics Core Facility of the University of Florence, within the context of the Molecular Medicine Facility of the Department of Experimental and Clinical Biomedical Sciences she directed. The facility, partially funded by AIRC Multiuser program and by her EU funds, is composed by high-throughput instrumentations as Gas Chromatography and Liquid Mass Mass Spectrometers, Seahorse analyzer, Oroboros High-Resolution Respirometry, behavioral animal asset-cages, hypoxia cabins and incubators, etc.
- She moved recently her research interests from the metabolism of primary tumors to the following steps, of tumor progression, including survival of metastatic circulating cells and colonization of new organs, thereby getting closer to the topic of the present proposal. Her work contributes to clarify that metabolic/nutritional signals are active in sustaining survival in circulation, after cells have escaped primary tumor environment. Moreover, she is actually involved in a project aiming to model the colonization of new organs by surviving cancer cells, scaffolding 3D microtissues with synthetic and ex vivo bioprinted matrices. She already set up stromalised prostate microtissues, confirming their ability to reproduce the metabolic interplay observed in animals. Top studies on this point are:
- Ippolito L, et al., Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer. EMBO Rep. 2024 Aug;25(8):3506-3531.
- Pranzini E, et al., Adapt and shape: metabolic features within the metastatic niche. Ippolito L, Pardella E, Giannoni E, Chiarugi P. Trends Endocrinol Metab. 2024 Aug 8:S1043-2760(24)00197-8
- Gangarossa, G., et al., Setup of an in vitro 3D stromalized prostate cancer model using gelatin microparticles, ACS Applied Bio Materials, submitted
Collaborations
Ildiko Szabo, Alessandro Carrer, University of Padua,
Carlo Catapano – IOR (Institute of Oncology, Bellinzona, Switzerland)
Silvia Giordano (IRCSS Candiolo)
Prof. Yingming Zhao, University of Chicago
Matteo Landriscina, Vincenza Conteduca, University of Foggia
Andrea Morandi, DSBSC – University of Florence
Sergio Serni, Luca Voltolini, Fabio Marra, DMSC – University of Florence
Cristina Nativi, Massimo Bonini, Dip. Chimica - University of Florence
Ultimo aggiornamento
05.03.2026