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Bert Vogelstein and co-workers identified DPEP1 in 2001 as one of the top six upregulated genes encoding a membrane or secreted protein in colorectal adenomas and cancers (CRCs). DPEP1 is a GPI-linked, zinc-dependent dipeptidase whose enzymatic activity includes processing extracellular glutathione and converting LTD4 to LTE4. Recently, it was reported to act nonenzymatically as a receptor for neutrophils on liver and lung endothelial cells and to influence monocyte migration. DPEP1 has been reported to have roles in cancer proliferation, invasion and metastasis. We recently showed that DPEP1 is the most abundant protein in small extracellular vesicles (sEVs) released from CRC cell lines by mass spectrometry and is present in a subset of EGFR+/CD81+ exosomes along with other clinically relevant biomarkers by fluorescence-activated vesicle sorting (FAVS) (Q Zhang et al., Nature Cell Biology 23:1240-1254, 2021). We also found that DPEP1/CEACAM5 double-positive exosomes are increased in the plasma from three CRC patients compared to normal controls. Immunohistochemical staining for DPEP1 in clinically well-annotated adenoma and CRC tissue microarrays has revealed staining in 27% of adenomas and 71% of CRCs, whereas no staining was observed in normal colonic tissue. Moreover, diffuse cytoplasmic staining in CRCs was associated with a worse progression-free and overall survival. We have now generated adenoma organoids, some of which express endogenous DPEP1 that localizes to the apical plasma membrane in 3D organoids and when cultured as polarized monolayers on Transwell filters. We plan to examine the bi-directional effects of cellular DPEP1 and DPEP1-containing EVs and freshly isolated neutrophils and/or their EVs in a co-culture system that is part of our recently funded Translational and Biological Science in Early Lesions (TBEL) NCI U54 grant. Citation Format: Matthew E. Bechard, Sarah E. Glass, Robert J. Coffey. Dipeptidase-1 is a highly upregulated protein in CRC exosomes: Potential clinical relevance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B030.

Cancer-derived extracellular vesicles, including exosomes, and exomere nanoparticles, are under intense investigation for cargo that may serve as clinical biomarkers and therapeutic targets. Here, we report the discovery of a new extracellular nanoparticle, termed supemeres. Supermeres are morphologically different from exomeres as determined by fluid-phase atomic force microscopy and display distinct uptake both in vitro and in vivo. In colorectal cancer (CRC) cell-derived supermeres, TGFBI is the most abundant protein and is linked to CRC progression and survival. Supermeres are enriched with cargo involved in multiple cancers including glycolytic enzymes, AGO2, shed MET and GPC1, and miR-1246. The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab-resistance, and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential cancer-related circulating biomarkers and therapeutic targets. Citation Format: Qin Zhang, Dennis K. Jeppesen, James N. Higginbotham, Sarah E. Glass, Jeffrey L. Franklin, Robert J. Coffey. Supermeres are functional extracellular nanoparticles replete with cancer biomarkers and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3850.