title: Adenovirus i-leader truncation bioselected against cancer-associated fibroblasts to overcome tumor stromal barriers.
abstract: Tumor-associated stromal cells constitute a major hurdle in the antitumor efficacy with oncolytic adenoviruses. To overcome this biological barrier, an in vitro bioselection of a mutagenized AdwtRGD stock in human cancer-associated fibroblasts (CAFs) was performed. Several rounds of harvest at early cytopathic effect (CPE) followed by plaque isolation led us to identify one mutant with large plaque phenotype, enhanced release in CAFs and enhanced cytotoxicity in CAF and several tumor cell lines. Whole genome sequencing and functional mapping identified the truncation of the last 17 amino acids in C-terminal end of the i-leader protein as the mutation responsible for this phenotype. Similar mutations have been previously isolated in two independent bioselection processes in tumor cell lines. Importantly, our results establish the enhanced antitumor activity in vivo of the i-leader C-terminal truncated mutants, especially in a desmotic fibroblast-embedded lung carcinoma model in mice. These results indicate that the i-leader truncation represents a promising trait to improve virotherapy with oncolytic adenoviruses.
authors.affiliation: Translational Research Laboratory, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Puig-Saus
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.forename: Ramon
authors.initials: R
authors.lastname: Alemany
authors.forename: Manel
authors.initials: M
authors.lastname: Cascalló
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017503:Adenovirus E3 Proteins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009154:Mutation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D012641:Selection, Genetic; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D017503:Adenovirus E3 Proteins