Abstract LB277: The p53-Reprimo-Hippo-YAP-p73 pathway: An extrinsic apoptosis mechanism for tumor suppression

Abstract The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a central role in tumor suppression. We have identified and characterized the molecular function of several novel p53 target genes, including Noxa, AEN, FUCA1, IER5, and PHLDA3 (Science, 2000; Cell, 2009; PNAS, 2014, etc). RPRM is a p53 target gene implicated in tumor suppression; however, its molecular function has remained largely elusive. Here we report that Reprimo, the protein product of RPRM, is secreted and extrinsically induces apoptosis in recipient cells (PNAS, 2025). We further identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as cell-surface receptors for Reprimo. Subsequent analyses revealed that upon binding to these receptors, Reprimo activates the Hippo-YAP-p73 axis, leading to apoptosis through transactivation of pro-apoptotic p73 target genes. In addition, we demonstrate that Reprimo converts YAP signaling from a tumor-promoting to a tumor-suppressive program by inhibiting the expression of YAP-driven oncogenic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. Collectively, these findings identify the p53-Reprimo-Hippo-YAP-p73 pathway as a novel extrinsic apoptosis mechanism essential for tumor suppression. The discovery of Reprimo as an innate tumor eliminator and its downstream signaling pathway provides a promising new avenue for the pharmacological treatment of cancer. Citation Format: Rieko Ohki. The p53-Reprimo-Hippo-YAP-p73 pathway: An extrinsic apoptosis mechanism for tumor suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB277.