Abstract 4760: Uncovering a highly transforming, Myc-stabilizing isoform of dipeptidase-1 in colorectal cancer

Abstract Protein isoforms play significant roles in cancer progression as they can impact localization, binding partners, and functions, especially when it comes to pro-tumorigenic properties. One protein in particular, dipeptidase-1 (DPEP1), was identified 25 years ago as a cell-surface protein upregulated in adenomas and colorectal cancers (CRCs) in comparison to normal colonic tissue. We have found that a diffuse staining pattern of DPEP1, not a cell-surface localization, leads to worse overall and progression-free survival for CRC patients. Spurred by the inconsistency of an intracellular DPEP1 staining pattern for a cell surface protein, we discovered two isoforms of DPEP1 that differ in their C-terminal sequence. This difference reflects an absence of a glycosylphosphatidylinositol anchorage signal sequence in a novel, undescribed isoform of DPEP1, that we have termed DPEP1 Isoform B. We found expression of DPEP1 Isoform B in CRC patient tissue samples which, upon immunohistochemical staining, revealed an intracellular localization of DPEP1 in cells. DPEP1 Isoform B expression transforms a non-tumorigenic cell line to form large, invasive tumors in nude mice and upregulates pro-tumorigenic gene programs including Myc targets, epithelial-to-mesenchymal transition, and angiogenesis as identified by RNA-seq. Surprisingly, in a CRC cell line, we find that DPEP1 Isoform B binds to Myc, increasing its half-life 2-fold. Utilizing TCGA data sets, we deployed a strategy to examine long transcripts and found that DPEP1 Isoform B was present in 91% of CRC patients, with 28% of patients having high expression of DPEP1 Isoform B. To contrast, DPEP1 Isoform A was present in 68% of CRC patients, having high expression in 26% of patients. Overall, our work demonstrates the discovery of a novel isoform of DPEP1, which given its high incidence in CRC, warrants further investigation as a predicative biomarker as well as a novel therapeutic target. Citation Format: Elizabeth Grace Fisher, Sarah E. Glass, Chelsie K. Sievers, Zheng Cao, Matthew E. Bechard, Samuel T. Ellis, Radhika Aramnadla, Ping Zhao, Ryan T. Smith, Yu Wang, James N. Higginbotham, Frank Revetta, M. Kay Washington, Martha J. Shrubsole, Qi Liu, Ken S. Lau, Bruce Aronow, Robert J. Coffey. Uncovering a highly transforming, Myc-stabilizing isoform of dipeptidase-1 in colorectal cancer [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 4760.