Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Daniela Taverna - PI
Full Professor of Molecular Biology, Dept. of Molecular Biotechnology and Health Sciences, University of Torino, Italy
- Francesca Orso, RTDB, external collaborator from UPO
- Sabrina Rizzolio, RTDA
- Lorena Quirico, Post-Doctoral fellow
- Martina Coco, PhD student
- Sara Cozzubbo, PhD student
- Andrea Caiola, Technician
- Alessia Gecchele MS student
- Alessia Marchese MS student
Research activity
Solid cancers are usually fatal to patients when cells can detach from primary tumors and form metastases in distant organs, which are responsible for about 90% of deaths. Based on Global Cancer Statistics, in 2018, 18.1 million cancer cases were diagnosed around the world and 9.5 million people died because of cancer. It has also been anticipated that by 2040, the number of new cases will rise to 29.5 million with the consequent death of 16.4 million patients. Tumor dissemination depends on the capability of cancer cells to detach from the primary tumor mass, travel in the blood circulation and finally seed and form metastasis in distant organs. The tumor microenvironment, formed by Cancer Associated Fibroblasts (CAFs), Mesenchymal Stem Cells (MSCs), Myeloid-derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs), Endothelial cells, Lymphocytes and Extracellular Matrix Proteins (ECMs), plays an essential role in malignancy. Thus, when investigating malignancy, it is essential focus on the microenvironment and on the cross-talk between tumor and stroma cells. Altered expression of protein-coding genes and of various RNAs, such as microRNAs (miRs), in tumor and stroma cells is linked to metastasis formation since it is responsible for biological and metabolic alterations. Because of the lack of efficacious therapies against tumor spreading, it is necessary to invest in new strategies to hit tumor and stroma cells to revert metabolic and adhesion/migration alterations. Malignant Melanoma (MM) is one of the most invasive, therapy-resistant and metastatic tumors, with a recent dramatic increased incidence. Similarly, malignant Breast Cancer (BC), in particular Triple Negative (TN) BC, is highly aggressive and often fatal because of frequent dissemination in distant organs since specific therapies are still missing. Our laboratory aims to understand the role and molecular mechanism of specific miRs in MM and BC progression and to develop new tumor/stroma specific therapeutic strategies. By comparing malignant versus non-malignant conditions, we could identify miR-214 and miR-148b as respectively upregulated and downregulated in MM and aggressive BC and, thanks to in vitro and in vivo functional studies, we evidenced the pro-metastatic function of miR-214 as well as the protective, anti-metastatic role of miR-148b. No major interventions on tumor growth were observed. Mechanistically, we evidenced that miR-214 could downregulate miR-148b and that, partially, the two small RNAs acted on the same axis. We know that, together, they can coordinate a metastatic molecular pathway which includes adhesion molecules (i.e. ALCAM, ITGA5) and transcription factors (TFAP2C) involved in the control of cell movement, invasion, extravasation and metastasis formation. We recently observed that high levels of miR-214 are present not only in tumor cells but also in the stroma counterparts, in particular in CAFs and that stroma miR-214 is highly relevant for cancer cell dissemination. See Fig. 1.
We know that tumor cells stimulate miR-214 expression in stroma cells via the activation of IL-6/STAT3 pathway. From a therapeutic point of view, we first attempted to block miR-214 by systemically delivering anti-miR-214 to mice carrying tumors and observed relevant inhibition of metastasis formation. Then, we generated tools for the specific delivery of miR-148b or of miR-214 inhibitors (sponges). Precisely, we designed conjugates made of an aptamer (a short oligonucleotide able to recognize specific targets on the cell membrane), which recognizes axl, a tyrosine kinase receptor highly expressed on MM and aggressive BC cells but not on the normal counterparts, linked to miR-148b or miR-214sponge as in Fig. 2.
We delivered axl-miR-148b (to upregulate miR-148b levels) or axl-miR-214sponge (to decrease miR-214 levels) to mice with tumors and obtained promising preclinical results suggesting that both conjugates can impair MM and TNBC dissemination, giving hope for a transfer to the clinics. We patented the conjugates and aim to analyze their relevance in clinical trials. These conjugates received the FIRST Intellectual Property Award (IPA) in Life Sciences and Healthcare, by the Italian Ministero dello Sviluppo Economico (MISE), in 2022.
Metabolic alterations play a major role in cancer progression and miRs are highly involved in metabolism. We have evidence that miR-214 and miR-148b are able to induce metabolic switches. Thus, we aim at identifying the molecular players associated with metabolism, which are controlled by these small RNAs and to generate therapeutic tools against them to use in combination with instruments able to hit miR-214 or increase miR 148b levels.
Fondazione CRT RF. 2018.1311 Bersagli terapeutici nella cura del melanoma, PI, 25,000 Euros
Progetti di Ateneo - Compagnia di San Paolo 2016/2018 - Macroarea Ricerca, New therapeutic targets and biomarkers in melanoma - Cofinanziamento di Ateneo, PI, 70,800 Euros
Progetti di Ateneo - Compagnia di San Paolo 2019/2021 - Mission 1.1 - Finanziamento ex-post, TArgeted Delivery of RNA Therapeutics to Cancer Cells (COST), PI, 45,000 Euros
Regione Piemonte FESR 2014-2020 - Salute e Benessere, 320-44 - DEFLeCT - Digital tEchnology For Lung Cancer Treatment, co-PI, 70,000 Euros
AIRC IG 2017 ID 20258-5 years, Role of miR-214 and miR-148b in tumor/stromal cell interactions and as therapeutic targets in cancer progression, PI, 587,000 Euros
AIRC IG 2022 ID 272054-5 years, miR-214 and miR-148-driven metabolic alterations in tumor progression and chimeric aptamer-based targeted therapy, PI, 739, 000 Euros
FISR 2021 Covid, Blood-based non-coding RNA Biomarkers to identify COVID-19 positive patients and predict disease progression focusing on systemic macrophagic reactions and their contribution to the cytokine storm, co-PI, 25,000 Euros
Ricerca sanitaria finalizzata - ministero della salute, con l’ospedale Gaslini, Genova, anno 2016 – 2023, Identification of new biomarkers for Oligoarticular Juvenile Idiopathic Arthritis by exosomal miRNA assessment in blood and synovial fluid, co-PI, 80,000 Euros.
Premio Intellectual Property Award 2021 IPA Prof.ssa D.Taverna Titolo: "Chimeric complex and is therapeutic uses in cancer metastasis treatment", PI, 10,000 Euros.
Progetti di Ateneo PoC Instrument - Compagnia di San Paolo 2019/2021, Complesso chimerico e suoi usi terapeutici, PI, 50,000 Euros.
Progetti di Ateneo, TOINPROVE/2023-2024, Aptamero CHImerico per il trattamento dei MElanomi REsistenti agli inibitori di BRAF (CHIMERE), PI 50,000 Euros
Progetti PNRR M4C2 Iniziativa 1.4 - Centri Nazionali (CN), RNA Therapy, 2022-2025, PI, 60, 000 Euros
MUR PRIN 2022, 2023-2025, Influence of stromal miR-425-5p and miR-214 in Triple Negative Breast Cancer Progression and aptamer-based targeting intervention, co-PI, 122,600 Euros.
Penna E., Orso F, Cimino D, Vercellino I, Grassi E, Quaglino E, Turco E, Taverna D. miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation. Cancer Res. 2013 Jul 1;73(13):4098-111. doi: 10.1158/0008-5472.CAN-12-3686. IF 12.701
Cuiffo BG, Campagne A, Bell GW, Lembo A, Orso F, Lien EC, Bhasin MK, Raimo M, Hanson SE, Marusyk A, El-Ashry D, Hematti P, Polyak K, Mechta-Grigoriou F, Mariani O, Volinia S, Vincent-Salomon A, Taverna D, Karnoub AE. MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis. Cell Stem Cell. 2014 Dec 4;15(6):762-74. doi: 10.1016/j.stem.2014.10.001. IF 24.633
Wicki A, Mandalà M, Massi D, Taverna D, Tang H, Hemmings BA, Xue G. Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling. Physiol Rev. 2016 Jul;96(3):805-29. doi: 10.1152/physrev.00024.2015. Review. IF 37.312
Orso F, Quirico L, Virga F, Penna E, Dettori D, Cimino D, Coppo R, Grassi E, Elia AR, Brusa D, Deaglio S, Brizzi MF, Stadler MB, Provero P, Caselle M, Taverna D. miR-214 and miR-148b targeting inhibits dissemination of melanoma and breast cancer. Cancer Res. 2016 Jun 21.pii:canres.1322.2015.doi: 10.1158/0008-5472.CAN-15-1322.IF 12.701.
Comunanza V, Corà D, Orso F, Consonni FM, Middonti E, Di Nicolantonio F, Buzdin A, Sica A, Medico E, Sangiolo D, Taverna D, Bussolino F. VEGF blockade enhances the antitumor effect of BRAFV600E inhibition. EMBO Mol Med. 201 Feb;9(2):219-237. doi: 10.15252/emmm.201505774. IF 12.137
Bellazzo A, Di Minin G, Valentino E, Sicari D, Torre D, Marchionni L, Serpi F, Stadler MB, Taverna D, Zuccolotto G, Montagner IM, Rosato A, Tonon F, Zennaro C, Agostinis C, Bulla R, Mano M, Del Sal G, Collavin L. Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells.Cell Death Differ. 2018 Jul;25(7):1224 1238. doi: 10.1038/s41418-018-0088-5. Epub 2018 Mar 22. IF 15.828
Dettori D, Orso F, Penna E, Baruffaldi D, Brundu S, Maione F, Turco E, Giraudo E, Taverna D. Therapeutic Silencing of miR-214 Inhibits Tumor Progression in Multiple Mouse Models. Mol Ther. 2018 Aug 1;26(8):2008-2018. doi: 10.1016/j.ymthe.2018.05.020. IF 11.454
Orso F, Quirico L, Dettori D, Coppo R, Virga F, Ferreira LC, Paoletti C, Baruffaldi D, Penna E, Taverna D. Role of miRNAs in tumor and endothelial cell interactions during tumor progression. Semin Cancer Biol. 2020 Feb;60:214-224. doi: 10.1016/j.semcancer.2019.07.024. Epub 2019 Aug 3. IF 15.707
Virga F, Cappellesso F, Stijlemans B, Henze AT, Trotta R, Van Audenaerde J, Mirchandani AS, Sanchez-Garcia MA, Vandewalle J, Orso F, Riera-Domingo C, Griffa A, Ivan C, Smits Laoui D, Martelli F, Langouche L, Van den Berghe G, Feron O,Ghesquière B, Prenen H, Libe C, Walmsley SR, Corbet C, Van Ginderachter JA, Ivan M, Taverna D*, Mazzone M*. Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation. Sci Adv. 2021 May 7;7(19):eabf0466. doi: 10.1126/sciadv.abf0466. IF 14.136. * co-last authors.
Orso F, Virga F, Dettori D, Dalmasso A, Paradzik M, Savino A, Pomatto MAC, Quirico L, Cucinelli S, Coco M, Mareschi K, Fagioli F, Salmena L, Camussi G, Provero P, Poli V, Mazzone M, Pandolfi PP, Taverna D. Stroma-derived miR-214 coordinates tumor dissemination. J Exp Clin Cancer Res. 2023 Jan 13;42(1):20. doi: 10.1186/s13046-022-02553-5. IF 12.658.
