Abstract 3989: Mutant p53 neomorphic activities drive organ-specific metastatic programs through distinct transcriptional networks

Abstract Mutations in the tumor suppressor p53 correlate with poor prognosis and high metastasis rates, which account for more than 90% of cancer-related mortality worldwide. Our recent work (Cancer Discovery PMC10841313), highlights that mutant p53 may exhibit neomorphic gain-of-function properties, driving squamous cell carcinoma (SCC) metastasis beyond its classic role via wild-type p53 loss. While our previous work and emerging studies have highlighted the neomorphic gain-of-function activities of mutant p53 in promoting metastasis, the tissue-specific transcriptional programs that underlie metastatic organotropism remain underexplored. To identify mutant p53-dependent mechanisms in facilitating organ-specific metastasis, we performed RNA-sequencing coupled with ChIP-sequencing on esophageal squamous cell carcinoma (ESCC)-derived lung and liver metastases harboring either mutant p53-R172H or p53 deletion. Analyses included differential gene expression (DEG), pathway enrichment, and comparisons between primary tumor and metastatic tumor transcriptomes. These studies were complemented by analyses of aero-digestive squamous cell carcinoma datasets from the AACR Project GENIE, TCGA, and tissue microarrays assessing mutant p53 in relation to patient survival and enriched molecular pathways. Mutant p53 contributed to distinct transcriptomic shifts in liver versus lung metastases. In lung metastases, 618 genes were upregulated and 667 downregulated dependent upon mutant p53-R172H, with enrichment in distinct immune response programs. By contrast, liver metastases showed 1,320 upregulated and 1,355 downregulated genes, with strong downregulation of interferon and inflammatory response pathways. Our analyses exhibited minimal overlap between up- or downregulated genes across tissues (103 shared downregulated and 77 shared upregulated genes), highlighting organ-specific p53-mediated transcriptional control. Furthermore, comparisons with primary tumors revealed subsets of DEGs uniquely dependent on p53-R172H across metastatic and primary contexts. Notably, only a small core set of genes (Acot1, Ldhb, Bcat1, Il18rap, Kif6, Paqr4, Il1rl1 and Cdc20) were upregulated in all three settings (primary, lung, liver), while most gene expressions were organ-specific. Overall, our results reveal novel insights into the mechanisms underlying mutant p53-mediated metastatic organotropism. These data highlight the necessity of incorporating the organ specific context metastatic cancers into therapeutic strategies driven by mutant p53. Citation Format: Gizem Efe, Raúl Navaridas, Katherine M. Cunningham, Dan Hasson, Chao Lu, James J. Manfredi, Carol L. Prives, Anil K. Rustgi. Mutant p53 neomorphic activities drive organ-specific metastatic programs through distinct transcriptional networks abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3989.