PTEN loss drives p53 LOH and immune evasion in a novel urothelial organoid model harboring p53 missense mutations.

Abstract

Despite missense mutation accounts for over 60% of p53 alterations while homozygous deletion (HOM) for only 5% or less in advanced bladder cancer cases, most of the previously reported mouse models are deficient of p53. Accordingly, few studies have addressed the mechanisms of missense mutation occurrence and its functional advantage over HOM in bladder cancer development. Organoids derived from Krt5-expressing mouse urothelium (K5-mUrorganoid) demonstrated the crucial role of Pten loss in driving loss of wild-type allele of Trp53 (Trp53^R172H/LOH), which conferred tumorigenic ability to K5-mUrorganoid in athymic mice. These tumors recapitulated the histological and genetic characteristics of the human basal-squamous subtype bladder cancer. Both Trp53^R172H/Δ; Pten^Δ/Δ and Trp53^Δ/Δ; Pten^Δ/Δ K5-mUrorganoids formed tumors in athymic mice, whereas only Trp53^R172H/Δ; Pten^Δ/Δ K5-mUrorganoid formed tumors even when directly inoculated in immunocompetent syngeneic mice. The absence of wild-type Trp53 was associated with upregulation of proliferative signaling, and the presence of a mutant Trp53 allele was associated with immune-excluded microenvironment. This study highlights the functional significance of p53 mutant LOH in bladder carcinogenesis conferring several hallmarks of cancer such as sustaining proliferative signaling and avoiding immune destruction, thus provides a novel immunocompetent mouse model of urothelial carcinoma harboring p53 mutations as a novel tool for cancer immunology research.