Experimental oncology
Cell signaling
This group studies the molecular events that regulate activation and signaling in normal and malignant cells. Different classes of transmembrane receptors can activate distinct signaling pathways; this will drive proliferation, differentiation or apoptosis depending on the nature of the receptor and the following signaling pathways. The investigation of these elements will potentially lead to the identification of proteins and mechanisms that may be exploited as novel therapeutic targets in oncology.
Research activity
Cell signaling Unit recently focused on B-cell receptor (BCR) and Toll-like receptors signaling in leukemia and lymphoma. Briefly, the group discovered that distinct BCR-signaling pathways are constitutively activated in a subset chronic lymphocytic leukemia, resembling a molecular signature of anergy; importantly, targeting anergy by using NFAT and MEK inhibitors triggered cell death.
The unit also found that distinct Toll-like receptors are expressed on chronic lymphocytic leukemia cells, and they are functionally involved in regulating NFkB activation, cell viability, proliferation and apoptosis; to note, the inhibitory receptor TIR8 is downregulated in malignant cells.
The unit also found that distinct Toll-like receptors are expressed on chronic lymphocytic leukemia cells, and they are functionally involved in regulating NFkB activation, cell viability, proliferation and apoptosis; to note, the inhibitory receptor TIR8 is downregulated in malignant cells.
Mantione ME, Sana I, Vilia MG, Riba M, Doglioni C, Larcher A, Capitanio U, Muzio M, SIGIRR Downregulation and Interleukin-1 Signaling Intrinsic to Renal Cell Carcinoma. Front Oncol. 2022 Jun 22;12:894413. doi: 10.3389/fonc.2022.894413
Sana I, Mantione ME, Angelillo P, Muzio, Role of NFAT in Chronic Lymphocytic Leukemia and Other B-Cell Malignancies. M.Front Oncol. 2021 Apr 1;11:651057.
Delvecchio VS, Sana I, Mantione ME, Vilia MG, Ranghetti P, Rovida A, Angelillo P, Scarfò L, Ghia P, Muzio M. Interleukin-1 receptor-associated kinase 4 inhibitor interrupts toll-like receptor signalling and sensitizes chronic lymphocytic leukaemia cells to apoptosis. Br J Haematol. 2020 May;189(3):475-488
Riva F, Ponzoni M, Supino D, Bertilaccio S, Polentarutti N, Massara M, Pasqualini F, Carriero R, Innocenzi A, Anselmo A, Veliz-Rodriguez T, Simonetti G, Anders H-J, Caligaris-Cappio F, Mantovani A, Muzio M*, Garlanda C*. IL1R8 Deficiency Drives Autoimmunity-Associated Lymphoma Development. Cancer Immunology Research 2019 Apr 24. doi: 10.1158/2326 6066.CIR-18-0698. * Co-corresponding authors
Gounari M, Ntoufa S, Gerousi M, Vilia MG, Moysiadis T, Kotta K, Papakonstantinou N, Scarfò L, Agathangelidis A, Fonte E, Ranghetti P, Nenou A, Xochelli A, Coscia M, Tedeschi A, Stavroyianni N, Muzio M*, Stamatopoulos K*, Ghia P*. Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment. Leukemia. 2019 Jan 3. doi: 10.1038/s41375-018-0335-2. (*last authors)
Fonte E, Vilia MG, Reverberi D, Sana I, Scarfò L, Ranghetti P, Orfanelli U, Cenci S, Cutrona G, Ghia P, Muzio M. TLR9 stimulation can induce IkappaBzeta expression and IgM secretion in chronic lymphocytic leukemia cells. Haematologica 2017 Nov; 102(11): 1901–1912.
Vilia MG, Tocchetti M, Fonte E, Sana I, Muzio M. Characterization of a long isoform of IL-1R8 (TIR8/SIGIRR). Eur Cytokine Netw. 2017 Jun 1;28(2):63-9.
Vilia MG, Fonte E, Veliz Rodriguez T, Tocchetti M, Ranghetti P, Scarfò L, Papakonstantinou N, Ntoufa S, Stamatopoulos K, Ghia P, Muzio M. The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia. Leuk Lymphoma. 2017;58(10):2419-25.
Ntoufa S, Vilia MG, Stamatopoulos K, Ghia P, Muzio M. Toll-like receptors signaling: A complex network for NF-κB activation in B-cell lymphoid malignancies. Semin Cancer Biol. 2016;39:15-25.
Fonte E, Agathangelidis A, Reverberi D, Ntoufa S, Scarfò L, Ranghetti P, Cutrona G, Tedeschi A, Xochelli A, Caligaris-Cappio F, Ponzoni M, Belessi C, Davis Z, Piris MA, Oscier D, Ghia P, Stamatopoulos K, Muzio M. Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation. Haematologica. 2015;100(11):1460-8.
Apollonio B, Scielzo C, Bertilaccio MT, Ten Hacken E, Scarfò L, Ranghetti P, Stevenson F, Packham G, Ghia P, Muzio M*, Caligaris-Cappio F*. Targeting B- cell anergy in chronic lymphocytic leukemia. Blood. 2013;121(19):3879-88. (*last authors)
Fonte E, Apollonio B, Scarfò L, Ranghetti P, Fazi C, Ghia P, Caligaris-Cappio F, Muzio M. In vitro sensitivity of CLL cells to fludarabine may be modulated by the stimulation of toll-like receptors. Clin Cancer Res. 2013; 19(2):367-79.
Ntoufa S, Vardi A, Papakonstantinou N, Anagnostopoulos A, Aleporou-Marinou V, Belessi C, Ghia P, Caligaris-Cappio F, Muzio M*, Stamatopoulos K. Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors. Mol Med. 2012;18:1281-91. (*corresponding author)
Arvaniti E, Ntoufa S, Papakonstantinou N, Touloumenidou T, Laoutaris N, Anagnostopoulos A, Lamnisou K, Caligaris-Cappio F, Stamatopoulos K, Ghia P, Muzio M*, Belessi C. Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenetic significance in specific subsets of patients. Haematologica. 2011;96(11):1644-52. (*corresponding author)
Bertilaccio MTS, Simonetti G, Dagklis A, Rocchi M, Veliz-Rodriguez T, Apollonio B, Mantovani A, Ponzoni M, Ghia P, Garlanda C, Caligaris-Cappio F, Muzio M. Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models. Blood 2011;118(3):660-9.
