EMID2 is a novel biotherapeutic for aggressive cancers identified by in vivo screening
-
Published:2024-01-10
Issue:1
Volume:43
Page:
-
ISSN:1756-9966
-
Container-title:Journal of Experimental & Clinical Cancer Research
-
language:en
-
Short-container-title:J Exp Clin Cancer Res
Author:
Cappelletto Ambra, Alfì Edoardo, Volf Nina, Vu Thi Van Anh, Bortolotti Francesca, Ciucci Giulio, Vodret Simone, Fantuz Marco, Perin Martina, Colliva Andrea, Rozzi Giacomo, Rossi Matilde, Ruozi Giulia, Zentilin Lorena, Vuerich Roman, Borin Daniele, Lapasin Romano, Piazza Silvano, Chiesa Mattia, Lorizio Daniela, Triboli Luca, Kumar Sandeep, Morello Gaia, Tripodo Claudio, Pinamonti Maurizio, Piperno Giulia Maria, Benvenuti Federica, Rustighi Alessandra, Jo Hanjoong, Piccolo Stefano, Del Sal Giannino, Carrer Alessandro, Giacca Mauro, Zacchigna SerenaORCID
Abstract
Abstract
Background
New drugs to tackle the next pathway or mutation fueling cancer are constantly proposed, but 97% of them are doomed to fail in clinical trials, largely because they are identified by cellular or in silico screens that cannot predict their in vivo effect.
Methods
We screened an Adeno-Associated Vector secretome library (> 1000 clones) directly in vivo in a mouse model of cancer and validated the therapeutic effect of the first hit, EMID2, in both orthotopic and genetic models of lung and pancreatic cancer.
Results
EMID2 overexpression inhibited both tumor growth and metastatic dissemination, consistent with prolonged survival of patients with high levels of EMID2 expression in the most aggressive human cancers. Mechanistically, EMID2 inhibited TGFβ maturation and activation of cancer-associated fibroblasts, resulting in more elastic ECM and reduced levels of YAP in the nuclei of cancer cells.
Conclusion
This is the first in vivo screening, precisely designed to identify proteins able to interfere with cancer cell invasiveness. EMID2 was selected as the most potent protein, in line with the emerging relevance of the tumor extracellular matrix in controlling cancer cell invasiveness and dissemination, which kills most of cancer patients.
Funder
Fondazione AIRC per la ricerca sul cancro ETS
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference52 articles.
1. Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022;12(7):3049–62. 2. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019;11:509. 3. Ruozi G, Bortolotti F, Falcione A, Dal Ferro M, Ukovich L, Macedo A, et al. AAV-mediated in vivo functional selection of tissue-protective factors against ischaemia. Nat Commun. 2015;6:7388. 4. Ruozi G, Bortolotti F, Mura A, Tomczyk M, Falcione A, Martinelli V, et al. Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library. Sci Transl Med. 2022;14(660):eabo0699. 5. Bortolotti F, Ruozi G, Falcione A, Doimo S, Dal Ferro M, Lesizza P, et al. In vivo functional selection identifies Cardiotrophin-1 as a Cardiac Engraftment factor for mesenchymal stromal cells. Circulation. 2017;136(16):1509–24.
|
|