Prof. Guglielmo Sorci
Prof. Francesca Riuzzi
Dr. Sara Chiappalupi
Dr. Laura Salvadori
Prof. Rosario Donato
Preclinical targeting of RAGE (receptor for advanced glycation end-products)
to counteract cancer cachexia
Granted by AIRC (Associazione Italiana per la Ricerca sul Cancro); Project #24762 (2021-2026)
Cachexia, a multifactorial syndrome affecting more than half patients with advanced cancer and responsible for ~20% of cancer-associated deaths, is still poorly understood and no standard cures are available. Muscle atrophy due to systemic inflammation and tumor-released factors is a major clinical feature of cachexia leading to weight loss, and worsening quality of life and patients’ response to anti-cancer therapy. The identification of valuable biomarkers of early cachexia is of great importance to treat patients in the reversible phase of the syndrome. RAGE (receptor for advanced glycation end-products) signaling concurs to muscle development and homeostasis, however in cancer conditions RAGE sustains hallmarks of cancer cachexia due to hyperstimulation by high serum levels of its ligands, S100B and HMGB1, which also induce muscle wasting per se.
Genetic ablation of RAGE in tumor-bearing mice translates into reduced serum levels of cachexia-inducing factors, delayed loss of muscle mass and strength, reduced tumor progression, and increased survival. Thus, molecular targeting of RAGE might represent a therapeutic strategy to counteract the cachectic syndrome.
Our project is aimed to: i) dissect the mechanism(s) used by RAGE to sustain cachexia in tumor, immune and muscle components; ii) investigate the effects of FPS-ZM1 (RAGE inhibitor) or pentamidine (S100B inhibitor) in comparison with glucocorticoids or ghrelin treatment or physical exercise, in adult, aged and under-chemotherapy tumor-bearing mice; iii) establish a correlation between preclinical models of cachexia and cachectic patients with respect to muscle RAGE and serum levels of RAGE ligands.
We expect: i) to identify the mechanism(s) through which RAGE sustains cachexia and in which component(s) (muscular or non-muscular); ii) that inactivation of RAGE using FPS-ZM1 and/or pentamidine reduces systemic inflammation and favours the maintenance of muscle mass and functionality in cancer conditions, even under chemotherapy treatment or during aging; and iii) to find a positive correlation between the severity of cachexia, RAGE expression in muscles and the serum levels of RAGE ligands in preclinical models and in cancer patients.
Pharmacological inhibition of RAGE activity might represent a promising approach to counteract muscle wasting in cancer conditions, and might be used as an exercise-mimetics in cachectic patients with elevated muscle weakness.
RAGE, sRAGE and/or RAGE ligands might represent potential biomarkers to monitor the cachectic stage and the efficacy of anti-cachectic treatments, which is of great importance as reliable biomarkers of cachexia are still lacking.
Use of microencapsulated Sertoli cells in Duchenne muscular dystrophy. Towards an application to human patients
Granted by Parent Project Onlus, Italy
Duchenne muscular dystrophy (DMD) is an X-linked disease due to lack of dystrophin, leading to progressive muscle degeneration, impaired locomotion and premature death. Persistent muscle degeneration is associated with a condition of chronic inflammation causing muscle necrosis and fibrosis.
Sertoli cells (SeC) have the ability to produce immunomodulatory and trophic factors. SeC have been long used to create an ectopic immune-privileged environment to prolong survival of co-transplanted cells. Encapsulation has represented an improvement for the use of SeC.
We reported that a single intraperitoneal injection of microencapsulated SeC (SeC-MC) is beneficial to dystrophic mdx mice. Injected SeC-MC behave as a drug-delivery system secreting factors that reach muscle tissue through the circulation, where reduce the inflammation and induce the expression of the dystrophin paralogue, utrophin, leading to rescue of muscle morphology and performance.
Although this novel therapeutic approach to DMD has translational potential (SeC are isolated from specific pathogens-free pigs, encapsulated in clinical grade alginate, injected with non-invasive procedure, and without any immunosuppression), further aspects need to be investigated that is the aim of this project: i) SeC-MC dose-response; ii) effects of SeC on canine and human dystrophic myoblasts in vitro; iii) morphology of SeC inside the microcapsules over time; iv) the role of SeC in inflammation using utrophin-deficient mdx (mdx/Utrn-/-) mice; and v) the safety of SeC treatment by the use of experimental models of infection and cancer.
The results will give us important information about SeC biology necessary in view of their possible application to DMD patients.
Multidisciplinary approach to the analysis of the functional alterations induced by microgravity in human satellite cells, and study of possible countermeasures
Granted by ASI (Italian Space Agency)
Long-time exposure to microgravity induces alteration of homeostasis in organs and tissues including skeletal muscles, which undergo atrophy with loss of mass and strength due to loss of muscle fibers and alteration of their composition. Particularly for long time flights such condition is of paramount relevance. Investigating the molecular mechanisms of muscle atrophy induced by microgravity is essential for establishing clinical approach/intervention.
Satellite cells (SC) are responsible for growth, maintenance and repair of the muscle tissue. The adult SC of muscle tissue that reside between the basal lamina and the sarcolemma have the ability to activate, proliferate and form new muscle fibers or repair damaged ones. The activity of SC is under the control of intracellular and extracellular factors that are spatially and temporally organized. Microgravity conditions may be able to induce muscle atrophy by influencing the biology and the functionality of the SC. The research objectives are: 1) to study the changes induced by microgravity in the biology of human SC; 2) to compare the effects induced in human SC during the simulated microgravity on Ground with those induced by the real microgravity onboard the International Space Station (ISS); 3) to evaluate the effects in murine muscle cells of muscle-specific overexpression of IGF-1 as countermeasure to microgravity-induced muscle atrophy.
The results of this project can be useful to understand any alterations at the level of property of SC of human skeletal muscle induced by exposure to microgravity, both simulated and real. The knowledge of the changes in the properties of SC, combined with changes in the ability of SC to respond to certain extracellular factors, will allow to design future interventions (nutritional and/or pharmacological) to fight the muscle wasting process induced by microgravity and encourage growth and maintenance of muscle mass during long-term space travel.
(The project is coordinated by Prof. Stefania Fulle, University of Chieti-Pescara, Italy, and involves the University Sapienza of Rome and the University of L'Aquila)
Inhibition of RAGE as a therapeutic approach to Duchenne muscular dystrophy
Granted by Duchenne Parent Project, the Netherlands
Duchenne muscular dystrophy (DMD) is an X-linked pathology characterized by progressive muscle degeneration and chronic inflammation that causes muscle necrosis and fibrosis. Indeed, DMD patients are treated with antiinflammatory steroids, despite their limited efficacy and undesired side effects. RAGE, a multiligand receptor involved in inflammation and myogenesis, is not expressed in adult muscle tissue, but it is highly expressed in immune cells, regenerating myofibers during muscle regeneration, and dystrophic muscle tissue.
To establish the effective role of RAGE in DMD muscles we generated a dystrophic (mdx) mouse lacking RAGE (mdx/Ager-/- mouse), which shows significantly reduced necrotic myofibers and immune cell infiltrate suggesting that targeting RAGE might result beneficial to DMD muscles.
The aims of the project are to characterize the mdx/Ager-/- mouse, and to test the effects of RAGE inhibition by the specific inhibitor, FPS-ZM1, in DMD animals as a therapeutic approach.
We will analyze muscles of mdx/Ager-/- mice at different ages, with particular focus on inflammatory cells. In mdx mice, we will analyze the effects in vitro and in vivo (i.p. injections) of different doses and durations of FPS-ZM1 treatment in comparison with glucocorticoids treatment to find an optimal condition for recovery of muscle morphology and performance. We will perform histological, immunohistochemical, western blot, FACS and PCR analyses of markers of inflammation, muscle differentiation, fibrosis, necrosis and autophagy, and functional evaluation. We expect that inhibition of RAGE in DMD animals by FPS-ZM1 results in reduced muscle inflammation, necrosis and fibrosis, and favors muscle functionality.
Evaluation of the efficacy of herbal preparations to counter induced muscular atrophy and sarcopenia. Formulation of a suitable herbal product.
Granted by Regione Umbria (A.R.CO. Fellowship)
In collaboration with Laboratori Biokyma Srl (Anghiari, Italy) (), leader in the production of officinal plants, and the research groups of Prof. Ferruccio Poli, University of Bologna (Bologna, Italy) and Prof. Stefania Fulle, University of Chieti-Pescara (Chieti, Italy). The project is aimed at developing herbal formulations useful in counteracting muscle atrophy associated with inflammatory diseases, use of steroid drugs or physiologically associated with aging.
Chiappalupi S.1, Sorci G.1, Vukasinovic A., Salvadori L., Sagheddu R., Coletti D., Renga G., Romani L., Donato R.2 and Riuzzi F.2 (2020) Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia. J. Cachexia Sarcopenia Muscle (Accepted for publication) 1Contributed equally; 2Shared senior authorship
Riuzzi F., Chiappalupi S., Arcuri C., Giambanco I., Sorci G.1 and Donato R.1 (2020) S100 proteins in obesity: liaisons dangereuses. Cell. Mol. Life Sci. 77:129-47. doi: 10.1007/s00018-019-03257-4; 1Shared senior authorship
Chiappalupi S., Salvadori L., Luca G., Riuzzi F., Calafiore R., Donato R. and Sorci G. (2019) Do porcine Sertoli cells represent an opportunity for Duchenne muscular dystrophy? Cell Proliferation 26:e12599. doi: 10.1111/cpr.12599
Riuzzi F.1, Sorci G.1, Arcuri C., Giambanco I., Bellezza I., Minelli A. and Donato R. (2018) Cellular and molecular mechanisms of sarcopenia: the S100B perspective. J. Cachexia Sarcopenia Muscle. Accepted for publication; 1Contributed equally
Riuzzi F.1, Sorci G.1, Sagheddu R., Chiappalupi S., Salvadori L. and Donato R. (2018) RAGE in the pathophysiology of skeletal muscle. J Cachexia Sarcopenia and Muscle. doi: 10.1002/jcsm.12350; 1Contributed equally
Sagheddu R., Chiappalupi S., Salvadori L., Riuzzi F., Donato R. and Sorci G. (2018) Targeting RAGE as a potential therapeutic approach to Duchenne muscular dystrophy. Hum. Mol. Genet. Doi: 10.1093/hmg/ddy288
Luca G., Arato I., Sorci G., Cameron D., Hansen B., Baroni T., Donato R., White D. and Calafiore R. (2018) Sertoli cells for cell transplantation: preclinical studies and future perspectives. Andrology 6(3): 385-95; dx.doi.org/10.1111/andr.12484
Donato R., Sorci G. and Giambanco I. (2018) S100A6. Encyclopedia of Signaling Molecules, 2nd Edition, Springer, pp. 4805-4813
Chiappalupi S., Salvadori L., Luca G., Riuzzi F., Calafiore R., Donato R. and Sorci G. (2017) Employment of microencapsulated Sertoli cells as a new tool to treat Duchenne muscular dystrophy. J. Funct. Morphol. Kinesiol. 2(4):47
Riuzzi F., Beccafico S., Sagheddu R., Chiappalupi S., Giambanco I., Bereshchenko O., Riccardi C., Sorci G.1 and Donato R.1 (2017) Levels of S100B protein drive the reparative process in acute muscle injury and muscular dystrophy. Sci. Rep. 7(1):1253; doi: 10.1038/s41598-017-12880-9; 1Shared Senior authorship
Donato R., Sorci G. and Giambanco I. (2017) S100A6 protein: functional roles. Cell. Mol. Life Sci. 74(15):2749-60; doi: 10.1007/s00018-017-2526-9
Donato R., Sorci G. and Giambanco I. (2017) Le proteine S100. Ligand Assay 22(1):11-44. Cover figure assigned
Chiappalupi S., Luca G., Mancuso F., Madaro L., Fallarino F., Nicoletti C., Calvitti M., Arato I., Falabella F., Salvadori L., Di Meo A., Bufalari A., Giovagnoli S., Calafiore R., Donato R. and Sorci G. (2016) Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice. Biomaterials 75:313-26; dx.doi.org/10.1016/j.biomaterials.2015.10.029
Chiappalupi S., Luca G., Mancuso F., Madaro L., Fallarino F., Nicoletti C., Calvitti M., Arato I., Falabella F., Salvadori L., Di Meo A., Bufalari A., Giovagnoli S., Calafiore R., Donato R. and Sorci G. (2015) Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice. Data in Brief 5:1015-21; dx.doi.org/10.1016/j.dib.2015.11.016
Matino D., Gargaro M., Santagostino E., Di Minno M.N.D., Castaman G., Morfini M., Rocino A., Mancuso M.E., Di Minno G., Coppola A., Talesa V.N., Volpi C., Vacca C., Orabona C., Iannitti R., Mazzucconi M.G., Santoro C., Tosti A., Chiappalupi S., Sorci G., Tagariello G., Belvini D., Radossi P., Landolfi R., Fuchs D., Boon L., Pirro M., Marchesini E., Grohmann U., Puccetti P., Iorio A., and Fallarino F. (2015) IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII. J. Clin. Invest. 125(10):3766-81; doi:10.1172/JCI81859
Beccafico S., Morozzi G., Marchetti M.C., Riccardi C., Sidoni A., Donato R. and Sorci G. (2015) Artesunate induces ROS-mediated apoptosis and counteracts tumor growth in vivo in embryonal rhabdomyosarcoma cells. Carcinogenesis 36(9):1071-83; doi:10.1093/carcin/bgv098
Alaggio R., Midrio P., Sgrò A., Piovan G., Guzzardo V., Donato R., Sorci G., Lago P., Gamba P.G. (2015) Congenital diaphragmatic hernia: focus on abnormal muscle formation. J. Pediatr. Surg. 50(3):388-93; doi:10.1016/j.jpedsurg.2014.08.005
Chiappalupi S., Riuzzi F., Fulle S., Donato R., Sorci G. (2014) Defective RAGE activity in embryonal rhabdomyosarcoma cells results in high PAX7 levels that sustain migration and invasiveness. Carcinogenesis 35:2382-92; doi: 10.1093/carcin/bgu176
Riuzzi F.1, Sorci G.1, Sagheddu R.1, Sidoni A., Alaggio R., Ninfo V., Donato R. (2014) RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation. J. Cell Sci. 127:1699-711; doi:10.1242/jcs.136259; 1Contributed equally
Faggi F., Mitola S., Sorci G., Riuzzi F., Donato R., Codenotti S., Poliani P.L., Cominelli M., Vescovi R., Rossi S., Calza S., Colombi M., Penna F., Costelli P., Perini I., Sampaolesi M., Monti E., Fanzani A. (2014) Phosphocaveolin-1 enforces tumor growth and chemoresistance in rhabdomyosarcoma. PLoS ONE 9(1):e84618; doi:10.1371/journal.pone.0084618
Iannitti R.G., Casagrande A., De Luca A., Cunha C., Sorci G., Riuzzi F., Borghi M., Galosi C., Massi-Benedetti C., Oury T.D., Cariani L., Russo M., Porcaro L., Colombo C., Majo F., Lucidi V., Fiscarelli E., Ricciotti G., Lass-Flörl C., Ratclif L., Esposito A., De Benedictis F.M., Donato R., Carvalho A., Romani L. (2013) Hypoxia promotes danger-mediated inflammation via RAGE in Cystic Fibrosis. Am. J. Resp. Crit. Care Med. 188(11):1338-50; doi:10.1164/rccm.201305-0986OC
Dormoy-Raclet V., Cammas A., Celona B., Lian X. J., van der Giessen K.1, Zivojnovic M., Brunelli S., Riuzzi F., Sorci G., Wilhelm B., Di Marco S., Donato R., Bianchi M. E. and Gallouzi I.-E. (2013) HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA. Nat. Commun. 4:2388; doi:10.1038/ncomms3388
Fanzani A., Monti E., Donato R. and Sorci G. (2013) Muscular dystrophies share pathogenetic mechanisms with muscle sarcomas. Trends Mol. Med. 19(9):546-54, doi: 10.1016/j.molmed.2013.07.001
Sorci G., Riuzzi F., Arcuri C., Tubaro C., Bianchi R., Giambanco I. and Donato R. (2013) S100B protein in tissue development, repair and regeneration. World J. Biol. Chem. 4(1): 1-12; All the authors contributed equally
Donato R., Riuzzi F. and Sorci G. (2013) Causes of elevated serum levels of S100B protein in athletes. Eur. J. Appl. Physiol. 113:819-20
Sorci G., Riuzzi F., Giambanco I. and Donato R. (2013) RAGE in tissue homeostasis, repair and regeneration. Biochim. Biophys. Acta – Mol. Cell Res. 1833:101-9
Donato R., Cannon B.R., Sorci G., Riuzzi F., Hsu K., Weber D.J. and Geczy C.L. (2013) Functions of S100 proteins. Curr. Mol. Med. 13:24-57
Riuzzi F.1, Sorci G.1, Sagheddu R. and Donato R. (2012) HMGB1/RAGE regulates muscle satellite cell homeostasis via p38 MAPK/myogenin-dependent repression of Pax7 transcription. J. Cell Sci. 125(6):1440-54. Cover figure assigned; 1Contributed equally
Riuzzi F.1, Sorci G.1, Beccafico S. and Donato R. (2012) S100B engages RAGE or bFGF/FGFR1 in myoblasts depending on its own concentration and myoblast density. Implications for muscle regeneration. PLoS ONE 7(1): e28700, doi:10.1371/journal.pone.0028700; 1Contributed equally
Cunha C., Giovannini G., Pierini A., Bell A.S., Sorci G., Riuzzi F., Donato R., Rodrigues F., Velardi A., Aversa F., Romani L., Carvalho A. (2011) Genetically-determined hyperfunction of the S100B/RAGE axis is a risk factor for aspergillosis in stem cell transplant recipients. PLoS ONE 6(11): e27962, doi: 10.1371/journal.pone.0027962
Riuzzi F.1, Sorci G.1 and Donato R. (2011) S100B protein regulates myoblast proliferation and differentiation by activating FGFR1 in a bFGF-dependent manner. J. Cell Sci. 124(14):2389-400; 1Contributed equally
Sorci G.1, Giovannini G.1, Riuzzi F., Bonifazi P., Zelante T., Zagarella S., Bistoni F., Donato R. and Romani L. (2011) The danger signal S100B integrates pathogen– and danger–sensing pathways to restrain inflammation. PLoS Pathog. 7(3):e1001315; 1Contributed equally
Beccafico S., Riuzzi F., Puglielli C., Mancinelli R., Fulle S., Sorci G. and Donato R. (2011) Human muscle satellite cells show age-related differential expression of S100B protein and RAGE. Age(Dordr) 33:523–541 (DOI 10.1007/s11357-010-9197-x)
Sorci G., Riuzzi F., Arcuri C., Bianchi R., Brozzi F., Tubaro C., Giambanco I. and Donato R. (2010) The many faces of S100B protein: when an extracellular factor inactivates its own receptor and activates another one. Italian J. Anat. Embryol. 115, 1:1/2 (Suppl.)
Danieli-Betto D., Peron S., Germinario E., Zanin M., Sorci G., Franzoso S., Sandonà D., and Betto R. (2010) Sphingosine 1-phosphate signaling is involved in skeletal muscle regeneration. Am. J. Physiol. – Cell Physiol. 298(3):C550-8
Donato R., Sorci G., Riuzzi F., Arcuri C., Bianchi R., Brozzi F., Tubaro C. and Giambanco I. (2009) S100B’s double life: Intracellular regulator and extracellular signal. Biochim. Biophys. Acta – Mol. Cell Res. 1793:1008–1022
Riuzzi F.1, Sorci G.1 and Donato R. (2007) RAGE expression in rhabdomyosarcoma cells results in myogenic differentiation and reduced proliferation, migration, invasiveness, and tumor growth. Am. J. Pathol. 171(3):947-961; 1 Contributed equally
Riuzzi F.1, Sorci G.1 and Donato R. (2006) The amphoterin (HMGB1)/receptor for advanced glycation end products (RAGE) pair modulates myoblast proliferation, apoptosis, adhesiveness, migration and invasiveness. Functional inactivation of RAGE in L6 myoblasts results in tumor formation in vivo. J. Biol. Chem. 281(12):8242-8253; 1 Contributed equally
Riuzzi F.1, Sorci G.1 and Donato R. (2006) S100B Stimulates Myoblast Proliferation and Inhibits Myoblast Differentiation by Independently Stimulating ERK1/2 and Inhibiting p38 MAPK. J. Cell. Physiol. 207:461-470; 1 Contributed equally
Businaro R., Leone S., Fabrizi C., Sorci G., Donato R., Lauro G.M. and Fumagalli L. (2006) S100B Protects LAN-5 Neuroblastoma Cells Against Aβ Amyloid Neurotoxicity Via RAGE Engagement at Low Doses But Increases Aβ Amyloid Neurotoxicity at High Doses. J. Neurosci. Res. 83:897-906
Sorci G., Riuzzi F., and Donato R. (2004) Amphoterin Stimulates Myogenesis and Counteracts the Anti-myogenic Factors Basic Fibroblast Growth Factor and S100B via RAGE Binding. Mol. Cell. Biol. 24(11):4880-4894
Sorci G., Riuzzi F., Agneletti A.L., Marchetti C. and Donato R. (2003) S100B inhibits myogenic differentiation and myotube formation in a RAGE-independent manner. Mol. Cell. Biol. 23(14):4870-4881
Rambotti M.G., Spreca A., Giambanco I., Sorci G., and Donato R. (2002) Ultracytochemistry as a tool for the study of the cellular and subcellular localization of membrane-bound guanylate cyclase (GC) activity. Applicability to both receptor-activated and receptor-independent GC activity. Mol. Cell. Biochem. 230:85-96
Adami C.1, Sorci G.1, Blasi E., Agneletti A.L., Bistoni F., and Donato R. (2001) S100B expression in and effects on microglia. Glia 33(2):131-142 ; 1 Contributed equally
Huttunen H.J., Kuja-Panula J., Sorci G., Agneletti A.L., Donato R., and Rauvala H. (2000) Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through RAGE activation. J. Biol. Chem. 275:40096-40105
Sorci G., Agneletti A.L., and Donato R. (2000) Effects of S100A1 and S100B on microtubule stability. An in vitro study using triton-cytoskeletons from astrocyte and myoblast cell lines. Neuroscience 99:773-783
Rende M., Brizi E., Sorci G., Bianchi R., Provenzano C., Bruno R., and Donato R. (1999) Regulation of the p75 neurotrophin receptor in a rat myogenic cell line (L6). Histochem. J. 31:589-601
Garbuglia M., Verzini M., Sorci G., Bianchi R., Giambanco I., Agneletti A.L., and Donato R. (1999) The calcium-modulated proteins, S100A1 and S100B, as potential regulators of the dynamics of type III intermediate filaments. Braz. J. Med. Biol. Res. 32:1177-1185
Sorci G., Bianchi R., Giambanco I., Rambotti M.G., and Donato R. (1999) Replicating myoblasts and fused myotubes express the calcium-regulated proteins S100A1 and S100B. Cell Calcium 25(2):93-106
Prof. Guglielmo Sorci
Sect. Human Anatomy, Dept. Experimental Medicine
University of Perugia
Piazz.le Lucio Severi 1, Bld. D, 1st Floor
06132 Perugia PG, Italy