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IOR

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affiliated to USI

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Molecular Oncology

Group Leader: Alimonti Andrea, MD

Cellular senescence is an irreversible cell growth arrest, observed in response to various insults including an abnormally high activity of oncogenes, suboptimal cells growth conditions and DNA damage. After its discovery and molecular characterization in vitro, it has only recently been recognized to specifically oppose tumor formation in various tissues, both in humans and in mice. Given the limited number of therapeutic approaches currently at our disposal in the fight against cancer, it is wise to explore the usefulness of a pro-senescence alternative for cancer therapy.

Our research is focused on the characterization of a novel type of cellular senescence response which is elicited by complete loss of the tumor suppressor PTEN, and on the identification of novel compounds with pro-senescence activity. Our aim is to develop the concept of pro-senescence therapy for cancer, from experimental evidences to clinic, investigating the efficacy of “pro-senescence” compounds in phase I clinical trials. This will also allow for the identification of senescence markers in human tumor samples to be used in clinic.

Members

Alimonti Andrea, MD, Group Leader
Attanasio Giuseppe, Lab Technician
Bancaro Nicolò, PhD Student
Bressan Silvia, PhD Student
Brina Daniela, PostDoc
Calì Bianca, PostDoc
Colucci Manuel, PhD Student
Cogo Francesca, Visiting Student (Master)
D’Ambrosio Mariantonietta, PhD Student
Gianfanti Federico, PhD Student
Iseli Cédric, Visiting Student (Bachelor)
Lai Ping, PhD Student
Li Yingrui, PhD Student
Liu Lei, PostDoc
Mosole Simone, Research Associate
Pasquini Emiliano, Lab Technician and Lab Manager
Pernigoni Nicolò, PhD Student
Troiani Martina, PhD Student
Valdata Aurora, Visiting Student (Bachelor)

Current Projects

  • Targeting cellular senescence in physiological, pathological and iatrogenic conditions
  • Development of senolytic therapies for chemotherapy-treated prostate cancer
  • Targeting tumor-infiltrating myeloid cells for prostate cancer therapy
  • Targeting the host microbiota to reverse therapeutic resistance in lethal prostate cancer

Relevant Publications

  • Pernigoni N, Zagato E, Calcinotto A, Troiani M, Mestre RP, Cali B, Attanasio G, Troisi J, Minini M, Mosole S, Revandkar A, Pasquini E, Elia AR, Bossi D, Rinaldi A, Rescigno P, Flohr P, Hunt J, Neeb A, Buroni L, Guo C, Welti J, Ferrari M, Grioni M, Gauthier J, Gharaibeh RZ, Palmisano A, Lucchini GM, D'Antonio E, Merler S, Bolis M, Grassi F, Esposito A, Bellone M, Briganti A, Rescigno M, Theurillat JP, Jobin C, Gillessen S, de Bono J and Alimonti A. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science (2021) 374, 216-224. https://www.ncbi.nlm.nih.gov/pubmed/34618582.
  • Guccini I, Revandkar A, D'Ambrosio M, Colucci M, Pasquini E, Mosole S, Troiani M, Brina D, Sheibani-Tezerji R, Elia AR, Rinaldi A, Pernigoni N, Rüschoff JH, Dettwiler S, De Marzo AM, Antonarakis ES, Borrelli C, Moor AE, Garcia-Escudero R, Alajati A, Attanasio G, Losa M, Moch H, Wild P, Egger G and Alimonti A. Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis. Cancer Cell (2021) 39, 68-82.e69. https://pubmed.ncbi.nlm.nih.gov/33186519/.
  • de Bono JS, Guo C, Gurel B, De Marzo AM, Sfanos KS, Mani RS, Gil J, Drake CG and Alimonti A. Prostate carcinogenesis: inflammatory storms. Nat Rev Cancer (2020) 20, 455-469. https://www.ncbi.nlm.nih.gov/pubmed/32546840.
  • Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, Carbone GM, Cavalli A, Pagano F, Ragazzi E, Prayer-Galetti T and Alimonti A. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol (2020) 31, 1040-1045. https://www.ncbi.nlm.nih.gov/pubmed/32387456.
  • Alajati A, D'Ambrosio M, Troiani M, Mosole S, Pellegrini L, Chen J, Revandkar A, Bolis M, Theurillat JP, Guccini I, Losa M, Calcinotto A, De Bernardis G, Pasquini E, D'Antuono R, Sharp A, Figueiredo I, Nava Rodrigues D, Welti J, Gil V, Yuan W, Vlajnic T, Bubendorf L, Chiorino G, Gnetti L, Torrano V, Carracedo A, Camplese L, Hirabayashi S, Canato E, Pasut G, Montopoli M, Ruschoff JH, Wild P, Moch H, De Bono J and Alimonti A. CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo. J Clin Invest (2020) 130, 2435-2450. https://www.ncbi.nlm.nih.gov/pubmed/32250342.
  • Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, Mosole S, Pasquini E, D'Antuono R, Masetti M, Zagato E, Chiorino G, Ostano P, Rinaldi A, Gnetti L, Graupera M, Martins Figueiredo Fonseca AR, Pereira Mestre R, Waugh D, Barry S, De Bono J and Alimonti A. Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer. Cell Rep (2019) 28, 2156-2168 e2155. https://www.ncbi.nlm.nih.gov/pubmed/31433989.
  • Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, De Bernardis G, Losa M, Mirenda M, Pasquini E, Rinaldi A, Sumanasuriya S, Lambros MB, Neeb A, Luciano R, Bravi CA, Nava-Rodrigues D, Dolling D, Prayer-Galetti T, Ferreira A, Briganti A, Esposito A, Barry S, Yuan W, Sharp A, de Bono J and Alimonti A. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature (2018) 559, 363-369. https://www.ncbi.nlm.nih.gov/pubmed/29950727.
  • Chen J, Guccini I, Di Mitri D, Brina D, Revandkar A, Sarti M, Pasquini E, Alajati A, Pinton S, Losa M, Civenni G, Catapano CV, Sgrignani J, Cavalli A, D'Antuono R, Asara JM, Morandi A, Chiarugi P, Crotti S, Agostini M, Montopoli M, Masgras I, Rasola A, Garcia-Escudero R, Delaleu N, Rinaldi A, Bertoni F, Bono J, Carracedo A and Alimonti A. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat Genet (2018) 50, 219-228. https://pubmed.ncbi.nlm.nih.gov/29335542/.
  • Revandkar A, Perciato ML, Toso A, Alajati A, Chen J, Gerber H, Dimitrov M, Rinaldi A, Delaleu N, Pasquini E, D'Antuono R, Pinton S, Losa M, Gnetti L, Arribas A, Fraering P, Bertoni F, Nepveu A and Alimonti A. Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence. Nat Commun (2016) 7, 13719. https://www.ncbi.nlm.nih.gov/pubmed/27941799.
  • Kalathur M, Toso A, Chen J, Revandkar A, Danzer-Baltzer C, Guccini I, Alajati A, Sarti M, Pinton S, Brambilla L, Di Mitri D, Carbone G, Garcia-Escudero R, Padova A, Magnoni L, Tarditi A, Maccari L, Malusa F, Kalathur RK, L AP, Cozza G, Ruzzene M, Delaleu N, Catapano CV, Frew IJ and Alimonti A. A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours. Nat Commun (2015) 6, 7227. https://www.ncbi.nlm.nih.gov/pubmed/26085373.
  • Alajati A, Guccini I, Pinton S, Garcia-Escudero R, Bernasocchi T, Sarti M, Montani E, Rinaldi A, Montemurro F, Catapano C, Bertoni F and Alimonti A. Interaction of CDCP1 with HER2 enhances HER2-driven tumorigenesis and promotes trastuzumab resistance in breast cancer. Cell Rep (2015) 11, 564-576. https://www.ncbi.nlm.nih.gov/pubmed/25892239.
  • Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, D'Antuono R, Montani E, Garcia-Escudero R, Guccini I, Da Silva-Alvarez S, Collado M, Eisenberger M, Zhang Z, Catapano C, Grassi F and Alimonti A. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature (2014) 515, 134-137. https://pubmed.ncbi.nlm.nih.gov/25156255/.
  • Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, Pinton S, Zhang J, Kalathur M, Civenni G, Jarrossay D, Montani E, Marini C, Garcia-Escudero R, Scanziani E, Grassi F, Pandolfi PP, Catapano CV and Alimonti A. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep (2014) 9, 75-89. https://www.ncbi.nlm.nih.gov/pubmed/25263564.
  • Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A, Salmena L, Sampieri K, Haveman WJ, Brogi E, Richardson AL, Zhang J and Pandolfi PP. Subtle variations in Pten dose determine cancer susceptibility. Nat Genet (2010) 42, 454-458. https://pubmed.ncbi.nlm.nih.gov/20400965/.

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