Cell Signaling in Tumor-Host interactions

The current research projects in our lab are deeply rooted in my post-doctoral training in investigating the regulation of the cell surface receptor dynamics and lipid signaling mediating the communication between cancer and the host (Cantley, Cell 1991; Graziani, J. Biol. Chem. 1991; Graziani, Biochem. J. 1992; Graziani, J. Biol. Chem. 1993; Ponzetto, Cell 1994; Graziani, J. Biol. Chem.  1996) . The two current major areas of interests in my lab 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 wasting 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 X-linked lymphoproliferative syndrome (XLP-1) 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 XLP-1 (Ruffo, Malacarne et al. Sci Transl Med, 2016). Through the years we have been investigating the regulation of TCR and Chimeric T cell Antigen Receptor (CAR) expression at the cell surface (Greco, Malacarne, et al. Sci Transl Med, 2022). We are currently investigating the hypothesis that DGKA and SAP, whose LOF mutations cause XLP, reciprocally regulate TCR signaling strength by controlling their trafficking to and from the T cell surface (Malacarne, Mula, ms. in preparation). In addition, in Chimeric Antigen Receptor (CAR) expressing cells we are showing a novel function of DGKA mediating a negative feedback mechanism, which restricts CAR T cell function and differentiation (Malacarne, ms. in preparation).
• By deprotecting the telomers of primary human T cells, we generated an in vitro immunosenescence model to investigate the molecular mechanisms underlying T cell senescence-associated dysfunction (Minea, ms in preparation).

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 Ghrelin 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, Ghrelin does not prevent muscle wasting in cancer cachexia
• We are currently investigating the molecular and cellular mechanisms of cancer cachexia. In particular, we recently showed that tumor-induced impairment of cAMP signaling and CREB1-dependent transcriptome mediates mitochondrial dysfunction in skeletal muscle. In addition, we showed in vitro and in vivo models, that reawakening cAMP signaling restores mitochondrial function, thus restoring skeletal muscle strength. The clinical relevance of this mechanism is underscored by the expression of CREB1-regulated genes in muscle biopsies from cancer cachectic patients (Angelino, Bodo, Nature Metabolism, 2025).