Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Mara Brancaccio - PI
Professor of Cell Biology in the Department of Molecular Biotechnology and Health Sciences, University of Torino.
- Matteo Sorge, Post-doc
- Pietro Poggio, phD student
- Francesca Zuppini, phD student
- Davide Acquarone, phD student
- Lucia Renzullo, phD student
- Francesca Tornatore, MD student
Research activity
The heat shock response (HSR) is an ancient and universal mechanism for preserving homeostasis and enhancing cell viability during stressful circumstances. This mechanism has played a vital role in the evolution and adaptation of organisms. My primary research interests are focused on chaperone proteins, which are pivotal players in the HSR. Chaperones are upregulated in response to various types of stress and are responsible for facing the emergency imposed by changes in environmental conditions. Furthermore, they are often essential for routine cellular maintenance tasks, acting as machineries for protein folding and the formation of supramolecular complexes.
Chaperone proteins in cancer growth and progression
Cancer cells experience various stresses in the tumor environment and they depend on a network of chaperone proteins to ensure their survival and to facilitate their adaptive responses. Chaperone inhibitors can be effective in causing damage and death to cancer cells, but they may also harm normal cells, as chaperones also serve essential housekeeping functions.
In addition to upregulate chaperone proteins, cancer cells release them in the extracellular milieu. Among these chaperones, Hsp90 is secreted by numerous cancer cells and human tumors. In the extracellular milieu its binds to various co-chaperones, forming complexes and machineries with specific tasks. These complexes often play a role in supporting tumor progression by aiding the chaperoning of extracellular client proteins and by enhancing cell survival and motility through interactions with surface receptors. However, it is important to note that extracellular HSP90 (eHSP90) also promotes anti-tumor immune response. By targeting specific co-chaperones, it becomes possible to separate the pro-tumor activity of eHSP90 from its ability to trigger anti-cancer immunity. In line with this approach, we generated an antibody that specifically targets the eHSP90 co-chaperone Morgana. This antibody is capable of disrupting the formation of complexes that induce cancer cell migration. In preclinical trials, treatment with this antibody has demonstrated the ability to inhibit metastasis and reduce tumor growth by promoting anti-cancer immunity (Figure 2).
Chaperone proteins in heart function
The rhythmic contraction of the heart is a result of the efficient performance of sarcomere structures, which are intricate assemblies of numerous proteins held together by non-covalent bonds. Chaperone proteins are responsible for ensuring the quality control and turnover of sarcomere proteins, thereby preserving their efficiency and enabling adaptation. Among these chaperones, Melusin stands out as a unique chaperone, expressed selectively in skeletal and cardiac muscles and acting as a mechanical stretch sensor. Melusin exerts its protective function through its interaction with the cytoplasmic region of beta 1 integrin, subsequently activating intracellular signaling pathways such as MAPK and PI3K/AKT. This signaling cascade leads to cardiomyocyte hypertrophy and enhanced cell survival. In light of these remarkable properties, Melusin overexpression in cardiomyocytes has shown promising results in improving myocardial function under various stress conditions, including pressure overload, myocardial infarction, and ischemia/reperfusion injury. Consequently, understanding the underlying molecular mechanisms by which Melusin exerts its protective effects is of great interest, and evaluating the potential of Melusin-based gene therapy approaches holds promise for the treatment of cardiomyopathy.
Skeletal muscle
Skeletal muscle, the largest organ in our body, consists of thousands of muscle fibers that come together to form muscles. The efficiency of muscle activity, similar to the heart, relies on the continuous and meticulous maintenance of sarcomeres. Muscle homeostasis, which is crucial for optimal muscle function, depends on a delicate balance between protein synthesis, assembly and degradation. Various factors, such as physical activity, nutrient availability, aging, and stressful situations like inflammatory diseases or cancer, influence these processes. When trophic pathways are activated through exercises or growth factors, protein synthesis surpasses degradation, resulting in muscle hypertrophy, the increase in muscle size. On the other hand, muscle atrophy occurs when the protein degradation machinery disassembles sarcomeres in response to physical inactivity or specific signals. Muscle atrophy leads to a reduction in muscle mass and strength. Melusin has been identified as a relevant player in protecting muscle tissue from atrophy. Our research aims to explore the molecular mechanisms through which Melusin exerts its protective activity and to elucidate its role in regulating trophic and atrophic pathways.
Stress into the wild
Alpine ecosystems are particularly vulnerable to the effects of climate change due to their unique and fragile nature. Rising temperatures, altered precipitation patterns, and changing snow cover dynamics profoundly impact the flora and fauna of these regions. Alpine organisms face the challenge of either adapting to the changing conditions or seeking alternative habitats to survive. Heat shock proteins play a crucial role in cellular stress responses and are known to be highly responsive to environmental changes. By monitoring the expression levels of HSPs, we can gain insights into the stress levels experienced by alpine organisms. We are setting methods to track the changes in HSP expression over time and perform longitudinal studies.
Our current research focuses on the characterization of extracellular chaperone complexes and of their roles in cancer growth and progression to design in innovative treatments. We are also actively involved in the identification of the indispensable house-keeping role of Morgana in mammals. Moreover, we are engaged in studying chaperone function in myocardial resilience and in skeletal muscle atrophy. Through a collaboration with Prof. Alessandro Bertero's group, we will utilize 3D-engineered tissues generated from human induced pluripotent stem cell (iPSCs) derived cardiomyocytes and skeletal muscle cells as innovative tools.
2021-2026: Principal investigator of the project “Targeting extracellular HSP90 complexes to fight cancer progression” funded by the Italian Association for Cancer Research (AIRC) – Investigator Grant 2020 Project IG 2020 (ID 24930) with €607,000/5 years (2021- 2025).
2018-2022: Head of research unit of the project - Digital Technology For Lung Cancer Treatment (DEFLeCT) funded by the Piedmont Region with 70.000 euro/3 years for my research unit.
2017-2019: Principal investigator of the 2016 University Project "Linking cardiac metabolism to inflammation" funded by Compagnia di San Paolo and the University of Turin with €70,800 / 2 years.
2016-2020: Head of research unit (proposing scientific coordinator: Giuseppe Lembo, La Sapienza University of Rome) of the PRIN 2015 Project "Characterization of adaptive or maladaptive influences of innate immune system on cardiac hypertrophic remodeling in response to pressure overload" funded by the Ministry of University and Research with €50,000/3 years for my research unit.
Brancaccio M, Guazzone S, Menini N, Sibona E, Hirsch E, De Andrea M, Rocchi M, Altruda F, Tarone G, Silengo L. Melusin is a new muscle-specific interactor for beta(1) integrin cytoplasmic domain. J Biol Chem. 1999 Oct 8;274(41):29282-8. doi: 10.1074/jbc.274.41.29282. PMID: 10506186
Brancaccio M, Fratta L, Notte A, Hirsch E, Poulet R, Guazzone S, De Acetis M, Vecchione C, Marino G, Altruda F, Silengo L, Tarone G, Lembo G. Melusin, a muscle-specific integrin beta1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat Med. 2003 Jan;9(1):68-75. doi: 10.1038/nm805. Epub 2002 Dec 23. PMID: 1249695
Tarone G, Brancaccio M. The muscle-specific chaperone protein melusin is a potent cardioprotective agent. Basic Res Cardiol. 2015 Mar;110(2):10. doi: 10.1007/s00395-015-0466-9. Epub 2015 Feb 5. PMID: 25653116.
Ferretti R, Palumbo V, Di Savino A, Velasco S, Sbroggiò M, Sportoletti P, Micale L, Turco E, Silengo L, Palumbo G, Hirsch E, Teruya-Feldstein J, Bonaccorsi S, Pandolfi PP, Gatti M, Tarone G, Brancaccio M. Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis. Dev Cell. 2010 Mar 16;18(3):486-95. doi: 10.1016/j.devcel.2009.12.020. PMID: 20230755.
Di Savino A, Panuzzo C, Rocca S, Familiari U, Piazza R, Crivellaro S, Carrà G, Ferretti R, Fusella F, Giugliano E, Camporeale A, Franco I, Miniscalco B, Cutrin JC, Turco E, Silengo L, Hirsch E, Rege-Cambrin G, Gambacorti-Passerini C, Pandolfi PP, Papotti M, Saglio G, Tarone G, Morotti A, Brancaccio M. Morgana acts as an oncosuppressor in chronic myeloid leukemia. Blood. 2015 Apr 2;125(14):2245-53. doi: 10.1182/blood-2014-05-575001. Epub 2015 Feb 12. PMID: 25678499.
Morotti A, Rocca S, Carrà G, Saglio G, Brancaccio M. Modeling myeloproliferative neoplasms: From mutations to mouse models and back again. Blood Rev. 2017 May;31(3):139-150. doi: 10.1016/j.blre.2016.11.004. Epub 2016 Nov 24. PMID: 27899218.
Fusella F, Ferretti R, Recupero D, Rocca S, Di Savino A, Tornillo G, Silengo L, Turco E, Cabodi S, Provero P, Pandolfi PP, Sapino A, Tarone G, Brancaccio M. Morgana acts as a proto-oncogene through inhibition of a ROCK-PTEN pathway. J Pathol. 2014 Oct;234(2):152-63. doi: 10.1002/path.4341. Epub 2014 Aug 6. PMID: 24615293.
Fusella F, Seclì L, Busso E, Krepelova A, Moiso E, Rocca S, Conti L, Annaratone L, Rubinetto C, Mello-Grand M, Singh V, Chiorino G, Silengo L, Altruda F, Turco E, Morotti A, Oliviero S, Castellano I, Cavallo F, Provero P, Tarone G, Brancaccio M. The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis. Nat Commun. 2017 Nov 21;8(1):1636. doi: 10.1038/s41467-017-01829-1. PMID: 29158506; PMCID: PMC5696377.
Fusella F, Seclì L, Cannata C, Brancaccio M. The one thousand and one chaperones of the NF-κB pathway. Cell Mol Life Sci. 2020 Jun;77(12):2275-2288. doi: 10.1007/s00018-019-03402-z. Epub 2019 Dec 6. PMID: 31811308.
Seclì L, Avalle L, Poggio P, Fragale G, Cannata C, Conti L, Iannucci A, Carrà G, Rubinetto C, Miniscalco B, Hirsch E, Poli V, Morotti A, De Andrea M, Turco E, Cavallo F, Fusella F, Brancaccio M. Targeting the Extracellular HSP90 Co-Chaperone Morgana Inhibits Cancer Cell Migration and Promotes Anticancer Immunity. Cancer Res. 2021 Sep 15;81(18):4794-4807. doi: 10.1158/0008-5472.CAN-20-3150. Epub 2021 Jun 30. PMID: 34193441.
