Integrated transcriptomics and proteomics data analysis identifies CDH17 as a key cell surface target in colorectal cancer

Abstract

Immunotherapy development against colorectal cancer (CRC) is hindered by the lack of cell surface target highly expressed in cancer cells but with restricted presence in normal tissues to minimize off-tumor toxicities. In this in silico analysis, a longlist of genes (n = 13,488) expressed in CRCs according to the Human Protein Atlas (HPA) database were evaluated to shortlist for potential surface targets based on the following prerequisites: (i) Absent from the brain and lung tissues to minimize the likelihood of neurologic and pulmonary toxicities; (ii) Restricted expression profile in other normal human tissues; (iii) Genes that potentially encode cell surface proteins and; (iv) At least moderately expressed in CRC cases. Fifteen potential targets were shortlisted and subsequently ranked according to the combination of their transcript and protein expression levels in CRCs derived from multiple datasets (i.e. DepMap, TCGA, CPTAC-2, and HPA CRCs). The top-ranked target with the highest and homogenous expression in CRCs was cadherin 17 (CDH17). Downstream analysis of CRC transcriptomics and proteomics datasets showed that CDH17 was significantly correlated with carcinoembryonic antigen expression. Moreover, CDH17 expression was significantly lower in CRC cases with high microsatellite instability, as well as negatively associated with immune response gene sets and the expression of MHC class I and II molecules. CDH17 represents an optimal target for therapeutic development against CRCs, and this study provides a novel framework to identify key cell surface targets for therapeutic development against other malignancies.