NON-COMMUNICABLE DISEASES / Cancer
Cancer, metastasis, cell signalling and cellular interactions, mechanotrasduction, metabolic reprogramming, p53, Pin1 prolyl isomerase, chemoresistance.
Description of Research
The Group studies the tumour microenvironment in relation to physical and biochemical cues that result in signalling that determines cell fate.
Tumors are ecosystems that evolve through changes (genetic/epigenetic) of cancer cells and interactions with the tumor microenvironment (TME). This cross talk is essential for tumor growth and metastatic dissemination, and involve physical (e.g. ECM stiffness) as well as biochemical cues that impact at several levels (e-g- metabolic, transcriptional, epigenetic) on key signaling pathways governing cell fate and response to therapy.
In recent years, we have focused on several aspects of cancer signalling, in particular on the study of p53/mut p53 networks and their interplay with YAP/TAZ transcription factors, as well as on how both mechanical (ECM rigidity) and biochemical signalling concur in the activation of these and other pathways leading to tumour growth, chemoresistance and metastastic outgrowth. Moreover, we have highlighted the role of key signal transduction events, such as the phosphorylation dependent prolyl isomerisation of a host of proteins by Pin1, in controlling proliferation of normal and cancer stem cells. We have also characterised a Pin1 covalent inhibitor.
Currently, we are interested in: i) investigating oncogenic induced metabolic alterations, in particular the cross talk between mechanotransduction and p53 dependent metabolic reprograming, and its impact on tumor initiation and progression; ii) deciphering the composition of the metastatic cell secretome and its interplay with the microenvironment to control metastasis outgrowth, and iii) understanding the role of Pin1 in epigenetics and chromatin regulation in cancer stem cells, metastasis and chemoresistance.
We use several model systems to carry out our studies: differentially engineered and gene edited 2D and 3D cellular systems grown in different matrices and in co-colture conditions, model organisms, patients derived organoids and others.
In 2021, we discovered that the prolyl isomerase PIN1 is required to preserve heterochromatin (Napoletano, F., et al Cell Rep. 2021). Importantly, PIN1 maintains the nuclear Lamin B architecture and promotes the anchoring of heterochromatin protein 1KK. on the nuclear envelope. This prevents relaxation of the heterochromatin under mechanical stress, which contributes to the ageing process.
Napoletano, F., Ferrari Bravo, G., Voto, I.A.P., Santin, S., Celora, L., Campaner, E., Dezi, C., Bertossi, A., Valentino, E., Santorsola, M., Rustighi, A., Fajner, V., Maspero, E., Ansaloni, F., Cancila, V., Valenti, C.F., Santo, M., Artimagnella, O.B., Finaurini, S., Gioia, U., Polo, S., Sanges, R., Tripodo, C., Mallamaci, A., Gustincich, S., d’Adda di Fagagna, F., Mantovani, F., Specchia, V., Del Sal, G. (2021). The prolyl-isomerase PIN1 is essential for nuclear Lamin-B structure and function and protects heterochromatin under mechanical stress. Cell Reports 36, 109694. Download article
Capaci, V., Bascetta, L., Fantuz, M., Beznoussenko, G.V., Sommaggio, R., Cancilla, V., Bisso, A., Campaner, E., Mironov, A.E., Jacek, R., Wiśniewski, J.R., Severino, L., Scaini, D., Bossi, F., Lees, J., Alon, N., Brunga, L., Malkin, D., Piazza, S., Collavin, L., Rosato, A., Bicciato, S., Tripodo, C., Mantovani, F., Del Sal, G. 2020. Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome. Nature Commun 11, article number 3945
Bertolio, R., Napoletano, F., Mano, M., Maurer-Stroh, S., Fantuz, M., Zannini, A., Bicciato, S., Sorrentino, G., Del Sal, G. 2019. Sterol Regulatory Element Binding Protein 1 couples mechanical cues and lipid metabolism. Nat Commun 10, 1326 doi.org/10.1038/s41467-019-09152 PubMed link
Ingallina, E., Sorrentino, G., Bertolio, R., Lisek, K., Zannini, A., Azzolin, L., Severino, L.U., Scaini, D., Mano, M., Mantovani, F., Rosato, A., Bicciato, S., Piccolo, S., Del Sal, G. 2018. Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis.Nat Cell Biol 20, 28-35 PubMed link
Campaner E, Rustighi A, Zannini A, Cristiani A, Piazza S, Ciani Y, Kalid O, Golan G, Baloglu E, Shacham S, Valsasina B, Cucchi U, Pippione AC, Lolli ML, Giabbai B, Storici P, Carloni P, Rossetti G, Benvenuti F, Bello E, D’Incalci M, Cappuzzello E, Rosato A, Del Sal G. 2017. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nat Commun 8, 15772 doi: 10.1038/ncomms15772 PubMed link
Sorrentino G, Ruggeri N, Zannini A, Ingallina E, Bertolio R, Marotta C, Neri C, Cappuzzello E, Forcato M, Rosato A, Mano M, Bicciato S, Del Sal G. 2017. Glucocorticoid receptor signalling activates YAP in breast cancer. Nat Commun 8, 14073 doi: 10.1038/ncomms14073 PubMed link