LAUSR

Tumor cell heterogeneity has been implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. We hypothesize that genes with low cell-to-cell transcriptional variability are more effective therapeutic targets, and use of variability as a metric will identify new metastatic regulators. Using single cell RNA sequencing, we demonstrate that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP/PEBP1) reduced overall transcriptional heterogeneity in TNBC xenograft tumors including oxidative phosphorylation genes. Consistent with a dependence on respiratory genes, metformin inhibited growth of RKIP-expressing but not RKIP-deficient tumors. Among genes with reduced transcriptional variability and increased mean in response to RKIP, we identified KMT5C as a novel epigenetic metastasis suppressor in TNBC. Taken together, these results indicate that analysis of gene expression variability along with mean can lead to effective target selection and provides an alternative strategy for identifying novel regulators of metastasis. Citation Format: Dongbo Yang, Christopher Dann, Andrea Valdespino, Lydia Robinson-Mailman, Mengjie Chen, Gábor Balázsi, Sebastian Pott, Marsha Rich Rosner. Gene expression heterogeneity reveals therapeutic targets and novel regulators of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 105.