Tumor-Host signaling interactions Lab

The current research projects in our lab are deeply rooted in my long-time interest in investigating the regulation of the cell surface receptor signaling mechanisms mediating the communication between cancer cells and their environment. The two current major areas of interests are to investigate 1) defective TCR signaling in both tumor-infiltrating T cells and aging T cells, and 2) the molecular mechanisms mediating skeletal muscle atrophy in cancer cachexia and aging-associated sarcopenia. 

1) defective TCR signaling in both tumor-infiltrating T cells and aging T cells 

Through the years, our lab pioneered the role of Diacylglycerol kinase alpha (DGKA) in oncogene signaling, by showing that its activation is required for tumorigenesis and invasion by regulating atypical PKC, Rho-family small GTPases and integrin recycling (Cutrupi, EMBO J, 2000; Baldanzi, Oncogene, 2004; Chianale, Mol.Biol.Cell, 2007, Baldanzi, Oncogene, 2008; Chianale, PNAS; 2010; Rainero, J.Cell.Biol. 2012). By virtual screening for DGKA inhibitors, in collaboration with pharmaceutical chemists, we identified a novel DGKA inhibitor (Velnati, Eur. J Med. Chem 2018; Velnati et al. 2019). In addition, we showed the negative regulation of DGKA activity upon T cells antigen stimulation, and its deregulation in immunoproliferative syndromes and leukemia (Bachiocchi, Blood, 2005; Baldanzi, J. Immunol. 2011). Indeed, we reported that DGKA targeting in vitro rescues defective TCR signaling strength and the pathology in in vitro and in vivo models of X-linked immunoproliferative syndrome (XLP) (Rufo, Malacarne et al. Sci Transl Med, 2016). Though the years we have developed interested in investigating the regulation of TCR and Chimeric T cell Antigen Receptor (CAR) expression at the cell surface (Greco, Malacarne, et al. Sci Transl Med, 2021). We are currently investigating the hypothesis that both DGKA and SAP, whose LOF mutations cause XLP, reciprocally regulate TCR and Chimeric T cell Antigen Receptor (CAR) signaling strength by controlling their trafficking to and from the T cell surface. We are also investigating the role of DGKA deregulation in driving defective TCR signaling and exhaustion in tumor-infiltrating T cells and in immune-aging. 

2) the molecular mechanisms mediating skeletal muscle atrophy in cancer cachexia and aging-associated sarcopenia. 

Upon our pioneering work reporting the first evidence that Ghrelin, an orexigenic hormone, acts as a survival factor in the myocardium by activating mitophagy through binding to a novel receptor yet to be identified (Baldanzi, J.Cell.Biol. 2002; Ruozi, Nature Commun. 2015), we then showed that in the skeletal muscle is part of a stress-induced adaptive response, which counteracts muscle wasting and sarcopenia, enhances Insulin sensitivity, and triggers muscle regeneration by activating satellite cells (Filigheddu, Mol.Biol.Cell. 2007, Porporato, J. Clin. Invest. 2013, Gortan-Capellari, Diabetes 2015, Reano, Angelino, Stem Cells, 2017, Angelino, Endocrine, 2019, Agosti, Aging, 2020). However, as Ghrelin does not prevent muscle wasting in cancer cachexia, we are currently investigating the role of tumor-induced impairment of cAMP signaling and CREB1-dependent transcriptome reprogramming driving mitochondrial dysfunction in cancer cachexia. Indeed, through in vitro and in vivo models, we have identified the molecular mechanisms linking tumor-released factors to defective cAMP signaling and mitochondrial dysfunction, and we are currently verifying these findings in human skeletal muscle biopsies. We are also planning to investigate the significance of these funding in aging associated  sarcopenia.