학술논문
EMID2 is a novel biotherapeutic for aggressive cancers identified by in vivo screening
Document Type
article
Author
Ambra Cappelletto; Edoardo Alfì; Nina Volf; Thi Van Anh Vu; Francesca Bortolotti; Giulio Ciucci; Simone Vodret; Marco Fantuz; Martina Perin; Andrea Colliva; Giacomo Rozzi; Matilde Rossi; Giulia Ruozi; Lorena Zentilin; Roman Vuerich; Daniele Borin; Romano Lapasin; Silvano Piazza; Mattia Chiesa; Daniela Lorizio; Luca Triboli; Sandeep Kumar; Gaia Morello; Claudio Tripodo; Maurizio Pinamonti; Giulia Maria Piperno; Federica Benvenuti; Alessandra Rustighi; Hanjoong Jo; Stefano Piccolo; Giannino Del Sal; Alessandro Carrer; Mauro Giacca; Serena Zacchigna
Source
Journal of Experimental & Clinical Cancer Research, Vol 43, Iss 1, Pp 1-14 (2024)
Subject
Language
English
ISSN
1756-9966
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.