Abstract 5179: Investigating the tumor suppressive role of RanBP9 in mice deficient in p53

Abstract RAN binding protein 9 (RanBP9) is a scaffolding protein that is essential for the formation a multi-subunit E3 ubiquitin ligase termed the C-terminal to Lis-1 homology (CTLH) complex. Multiple groups have identified the CTLH complex in regulating a broad range of biological processes including cell cycle, cell proliferation, and metabolism. Various studies have demonstrated that RanBP9 functions as a tumor suppressor, but none have shown whether the loss of RanBP9 can initiate spontaneous tumor formation. Here, we investigated the tumor suppressive role of RanBP9 in C57BL/6 mice. Bulk RNA sequencing (RNA-seq) analysis of 1-month-old RanBP9-/- mice liver identified an upregulation of several oncogenic signaling genes. Although RanBP9-/- mice displayed a shortened lifespan, these mice did not develop spontaneous tumors suggesting that additional genetic perturbations are required for tumor development. Next, we conducted an observational study in mice with RanBP9+/-: Trp53+/- (R9; p53+/-) and RanBP9-/-: Trp53-/- (R9; p53-/-) genotypes. These mice were monitored over 17 months for the development of spontaneous tumors. The primary endpoint was defined as the development of a visible mass (>1.5 cm) or symptoms of cancer. R9; p53+/- mice (n=23) developed sarcomas at an earlier time compared to control p53+/- mice (n=18; p<0.05). R9; p53+/- mice displayed altered tumor spectrum with increased frequency in soft tissue sarcoma (STS) development. H&E analysis of tumor biopsies revealed increased mitotic activity of sarcomas derived from R9; p53+/- mice compared to control p53+/- mice. We observed no significant difference in tumor incidence and altered tumor spectrum in R9; p53-/- mice compared to control p53-/- mice. Analysis of TCGA sarcoma database revealed a correlation between low gene expression of CTLH complex genes and reduced survival in sarcoma patients. Our data indicates that loss of RanBP9 alone is insufficient to initiate tumor development. However, the heterozygous loss of RanBP9 and p53 promotes increased STS development. Ongoing efforts are to further characterize R9; p53+/- tumors and identify the mechanism to understand how the loss of CTLH activity contributes to sarcoma development in the absence of p53. Our findings may support the development of anti-cancer therapeutics that activates RanBP9-CTLH complex activity. Citation Format: Brianna Gonga-Cave, Gabriel Onea, Xu Wang, Sean Cregan, Patti Kaiser, Caroline Schild-Poulter. Investigating the tumor suppressive role of RanBP9 in mice deficient in p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5179.