Molecular mechanisms of cancer pathology (PI Trerotola)
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Principal Investigator
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Prof. Trerotola’s Workgroup investigates the molecular mechanisms that underlie human cancer progression. Focus of our studies is Trop-2, a transmembrane glycoprotein strongly overexpressed in most human cancers of epithelial origin. We discovered that Trop-2 is a key driver of tumor growth and malignancy, and regulates several mechanisms that ultimately lead to metastatic dissemination, such as intercellular adhesions, integrin-dependent migration on extracellular matrices, and cell proliferation. Using next generation technologies, we are now investigating in detail how hubs and nodes of this complex signaling network are modulated by Trop-2 in various human cancer types, including cancer of colon, pancreas, prostate and breast, and how Trop-2 can be targeted with specific therapeutic strategies.
The Telethon Foundation supports a specific line of research of our group, aimed at defining the role of TDark glycoproteins in onset and progression of specific rare diseases and at developing new strategies for a broad-spectrum rescue of secretion their mutated, disease-associated variants (https://www.telethon.it/en/what-we-do/research/projects-funded/broad-spectrum-rescue-of-secretion-of-tdark-glycoprotein-mutants/)
Trop-2 is a transmembrane receptor found overexpressed in most human carcinomas, and since several years its expression has been correlated with disease aggressiveness. We and others have demonstrated that Trop-2 regulates tumor growth and metastatic dissemination through modulation of cell-extracellular matrix (ECM) interactions, cell-cell adhesions and cytoskeletal dynamics. Our group established various nation-wide and international collaborations with leaders in the field of proteomics and bioinformatics in order to define the Trop-2 complex signaling network in human cancer. Proteomic/phosphoproteomic profiling of cancer cells in vitro and human tumor samples are revealing important mediators of the Trop-2 function in human cancer progression. Moreover, transcriptomics/next-generation sequencing and bioinformatic/machine learning analysis of wild type and mutant Trop-2 expressing cells and tumors are now allowing to identify the key signaling hubs of the Trop-2 network in vivo for tumor growth and metastatization, and define structure-function relationships.READ MORE
Ongoing Research Projects
1. Signaling Network of Trop-2 in human cancer progression
Project Leaders: Prof. Marco Trerotola and Dr. Emanuela Guerra
Trop-2 is a transmembrane signal transducer that induces cancer progression. We and others have shown that the pro-oncogenic Trop-2 signalling occurs through regulation of expression and activity of cyclin D1, ERK, NFkB, Akt, FAK, Rac1 and integrins. However, the molecular mechanics and functional impact of Trop-2 in cancer progression remain elusive.
The Trop2/TACSTD2 gene was never observed to undergo gene mutations in cancer, indicating that alternative molecular mechanisms may be responsible for the functional derangement of Trop-2. We have recently demonstrated that a proteolytic cleavage of Trop-2 induces a profound rearrangement of the Trop-2 structure, and activates the molecule to induce cancer cell growth. We found that no activatory Trop-2 cleavage is detectable in normal tissues, whereas the majority of tumors, including cancers of skin, ovary, colon and breast, show cleavage. Coimmunoprecipitation and mass spectrometry analysis have revealed various proteases as potentially involved in this processing. Among them, we have identified that ADAM10 is a major proteolytic enzyme of Trop-2 and modulates its activity during tumor progression. Indeed, inhibition of ADAM10 expression or activity leads to a significant reduction of the Trop-2 cleavage and to a correspondingly lower effect on cancer cell growth. Reference: Trerotola M. et al., Neoplasia 23(4): 415-428 (2021).READ MORE
Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas
2. Role of Trop-2 in cancer metastasis
Project Leaders: Prof. Marco Trerotola and Dr. Emanuela Guerra
We are currently investigating in depth newly discovered functions of Trop-2 for modulation of malignant progression of human tumors. We use advanced laboratory approaches, from time-lapse confocal microscopy on 3D cancer cell spheroids to studies of tumor progression in vivo using murine models.
We have previously shown that Trop-2 can induce cancer cell migration on extracellular matrix integrin ligands, and that the surrounding mechanisms involve mislocalization of a5b1 integrin at cell-substrate contacts (also known as focal adhesions). This effect was also demonstrated in vivo through intracardiac injection of prostate cancer cells in murine models and monitoring of metastatic dissemination to distant organs. Significant correlation of Trop-2 overexpression with prognosis of cancer patients is observed at RNA and protein levels, for a potentially strong clinical impact of these findings. Reference: Trerotola M. et al., Oncotarget 6(16):14318-28 (2015). Trerotola M. et al., Cancer Research, May 15;73(10):3155-67 (2013). Trerotola M. et al., Journal of Cellular Physiology, Nov;227(11):3670-3677 (2012).READ MORE
- Trerotola M., Guerra E., Ali Z., Aloisi AL., Ceci M., Simeone P., Acciarito A., Zanna P., Vacca G., D’Amore A., Boujnah K., Garbo V., Moschella A., Lattanzio R., and Alberti S. Trop-2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis Neoplasia (2021) PMID: 33839455.
- Vergara D., Verri T., Damato M., Trerotola M., Simeone P., Franck J., Fournier I., Salzet M., Maffia M. A hidden human proteome signature characterizes the Epithelial Mesenchymal Transition program. Current Pharmaceutical Design (2020) PMID: 31995001.
- Vergara D., Simeone P., Damato M., Maffia M., Lanuti P. and Trerotola M. The cancer microbiota: EMT and inflammation as shared molecular mechanisms associated with plasticity and progression. Journal of Oncology (2019) Article ID: 1253727 PMID: 31772577.
- Relli V., Trerotola M., Guerra E., Alberti S. Abandoning the Notion of Non-Small Cell Lung Cancer. Trends in Molecular Medicine 25(7): 585-594 (2019). PMID: 31155338.
- Simeone P., Trerotola M., Franck J., Tristan C., Marchisio M., Fournier I., Salzet M., Maffia M. and Vergara D. The multiverse nature of epithelial to mesenchymal transition (Review). Seminars in Cancer Biology 58 (2019): 1-10. PMID: 30453041.
- Relli V., Trerotola M., Guerra E. and Alberti S. Distinct lung cancer subtypes associate to distinct drivers of tumor progression. Oncotarget 9(85): 35528-35540 (2018) PMID: 30473748.
- Avellini C, Licini C, Lazzarini R, Gesuita R, Guerra E, Tossetta G, Castellucci C, Giannubilo SR, Procopio A, Alberti S, Mazzucchelli R, Olivieri F,Marzioni D. The trophoblast cell surface antigen 2 and miR-125b axis in urothelial bladder cancer. Oncotarget. 2017 Apr 25;8(35):58642-58653. PMID: 28938585.
- Vergara D., Stanca E., Guerra F., Priore P., Gaballo A., Franck J., Simeone P., Trerotola M., De Domenico S., Fournier I., Bucci C., Salzet M., Giudetti AM. and Maffia M. β-catenin knockdown affects mitochondrial biogenesis and lipid metabolism in breast cancer cells. Frontiers in Physiology 8:544 (2017). PMID: 28798698.
- Guerra E, Piantelli M, Alberti S. Comment on "Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice". Sci Transl Med. 2016 Aug 3;8(350):350le2. PMID: 27488894.
- Guerra E, Cimadamore A, Simeone P, Vacca G, Lattanzio R, Botti G, Gatta V, D'Aurora M, Simionati B, Piantelli M, Alberti S. p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading. BMC Cancer. 2016 Aug 18;16:649. PMID: 27538498.
- Vergara D., Simeone P., Franck J., Trerotola M., Giudetti A., Capobianco L., Tinelli A., Bellomo C., Fournier I., Gaballo A., Alberti S., Salzet M. and Maffia M. Translating epithelial mesenchymal transition markers into the clinic: Novel insights from proteomics (Review). EuPa Open Proteomics 10: 31-41 (2016). PMID: 29900098.
- Guerra E., Trerotola M., Tripaldi R., Aloisi AL., Simeone P., Sacchetti A., Relli V., D’Amore A., La Sorda R., Lattanzio R., Piantelli M. and Alberti S. Trop-2 induces tumor growth through Akt and determines sensitivity to Akt inhibitors. Clinical Cancer Research 22(16): 4197-4205 (2016) PMID: 27022065.
- Li Y, Melnikov AA, Levenson V, Guerra E, Simeone P, Alberti S, Deng Y. A seven-gene CpG-island methylation panel predicts breast cancer progression. BMC Cancer. 2015 May 19;15:417. PMID: 25986046.
- Talati PG., Gu L., Ellsworth EM., Girondo MA., Trerotola M., Hoang DT., Leiby B., Dagvadorj A., McCue PA., Lallas CD., Trabulsi EJ., Gomella L., Aplin AE., Languino LR., Fatatis A., Rui H., Nevalainen MT. Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer. The American Journal of Pathology 185(9): 2505-2522 (2015). PMID: 26362718.
- Trerotola M., Relli V., Simeone P. and Alberti S. Epigenetic inheritance and the missing heritability (Review). Human Genomics 9:17 (2015). PMID: 26216216.
- Trerotola M., Ganguly KK., Fazli L., Fedele C., Lu H., Dutta A., Liu Q., De Angelis T., Riddell LW., Riobo NA., Gleave ME., Zoubeidi A., Pestell RG., Altieri DC. and Languino LR. Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts. Oncotarget 6(16):14318-28 (2015). PMID: 26015409.
- Vergara D., Simeone P., Latorre D., Cascione F.; Leporatti S., Trerotola M., Giudetti A.M., Capobianco L., Lunetti P., Rizzello A., Rinaldi R., Alberti S. and Maffia M. Proteomics analysis of E-Cadherin knockdown in epithelial breast cancer cells. Journal of Biotechnology, 202: 3-11 (2015). PMID: 25449012.
- Simeone P., Trerotola M., Urbanella A., Lattanzio R., Ciavardelli D., Di Giuseppe F., Eleuterio E., Sulpizio M., Eusebi V., Pession A., Piantelli M. and Alberti S. A unique four-hub protein cluster associates to glioblastoma progression. PLoS One, 9(7): e103030 (2014). PMID: 25050814.
- Ambrogi F., Fornili M., Boracchi P., Trerotola M., Relli V., Simeone P., La Sorda R., Lattanzio R., Querzoli P., Pedriali P., Piantelli M., Biganzoli E. and Alberti S. Trop-2 is a determinant of breast cancer survival. PLoS One, 8(5): e96993 (2014). PMID: 24824621.
- Sayeed A., Fedele C., Trerotola M., Ganguly KK. and Languino LR. IGF-IR promotes prostate cancer growth by stabilizing α5β1 integrin protein levels. PLoS One, 8(10): e76513 (2013). PMID: 24130778.
- Trerotola M., Jernigan D.L., Liu Q., Siddiqui J., Fatatis A. and Languino LR. Trop-2 promotes prostate cancer metastasis by modulating β1 integrin functions. Cancer Research, May 15;73(10):3155-67 (2013). PMID: 23536555.
- Guerra E., Trerotola M., Aloisi AL., Tripaldi R., Vacca G., La Sorda R., Lattanzio R., Piantelli M. and Alberti S. The Trop-2 signalling network in cancer growth. Oncogene, Mar 21; 32(12):1594-600 (2013). PMID: 22562244.
- Trerotola M., Cantanelli P., Guerra E., Tripaldi R., Aloisi AL., Bonasera V., Lattanzio R., de Lange R., Weidle UH., Piantelli M. and Alberti S. Up-regulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene, Jan 10; 32(2):222-233 (2013). PMID: 22349828.
- Guerra E, Lattanzio R, La Sorda R, Dini F, Tiboni GM, Piantelli M, Alberti S. mTrop1/Epcam knockout mice develop congenital tufting enteropathy through dysregulation of intestinal E-cadherin/β-catenin. PLoS One. 2012;7(11):e49302. PMID: 23209569.
- Plebani R., Oliver GR., Trerotola M., Guerra E., Cantanelli P., Apicella L., Emerson A., Albiero A., Harkin PD., Kennedy RD. and Alberti S. Long-range transcriptome sequencing reveals cancer cell growth regulatory chimeric mRNAs. Neoplasia, Nov;14(11):1087-1096 (2012). PMID: 23226102.
- Trerotola M., Li J., Alberti S., Languino LR. Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis. Journal of Cellular Physiology, Nov;227(11):3670-3677 (2012). PMID: 22378065.
- Sayeed A., Alam N., Trerotola M., Languino LR. Insulin-like growth factor 1 stimulation of androgen receptor activity requires β(1A) integrins. Journal of Cellular Physiology, Feb;227(2):751-758 (2012). PMID: 21465482.
- Saxena P., Trerotola M. *, Wang T., Li J., Sayeed A., VanOudenhove J., Adams DS., Fitzgerald TJ., Altieri DC. and Languino LR. PSA regulates Androgen Receptor expression in prostate cancer cells. Prostate, May 15;72(7):769-776 (2012). * co-first author PMID: 21956655.
- Trerotola M., Rathore S., Goel HL., Li J., Alberti S., Piantelli M., Adams D., Jiang Z. and Languino LR. CD133, Trop-2 and α2β1 Integrin Surface Receptors as Markers of Putative Human Prostate Cancer Stem Cells. American Journal of Translational Research, 2(2):135-144 (2010). PMID: 20407603.
- Guerra, E., Trerotola, M., Dell' Arciprete, R., Bonasera, V., Palombo, B., El-Sewedy, T., Ciccimarra, T., Crescenzi, C., Lorenzini, F., Rossi, C., Vacca, G., Lattanzio, R., Piantelli, M. and Alberti, S. A bicistronic CYCLIN D1-TROP2 mRNA chimera demonstrates a novel oncogenic mechanism in human cancer. Cancer Research, Oct 1;68(19):8113-8121 (2008). PMID: 18829570.
- Zanna, P., Trerotola, M., Vacca, G., Bonasera, V., Palombo, B., Guerra, E., Rossi, C., Lattanzio, R., Piantelli, M. and Alberti, S. Trop-1 are conserved growth stimulatory molecules that mark early stages of tumor progression. Cancer, Jul 15;110(2):452-464 (2007). PMID: 17559145.
- Nasr AF, Nutini M, Palombo B, Guerra E, Alberti S. Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene. Oncogene. 2003 Mar 20;22(11):1668-77. PMID: 12642870.
