Patient-Specific Pharmacogenomics demonstrates xCT as Predictive Therapeutic Target in Colon Cancer with Possible Implications in Tumor Connectivity

Colorectal cancer (CRC) represents the third-leading cause of cancer-related deaths. Knowledge covering diverse cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present an in-depth comparative mRNA-seq analysis of tissue samples from 32 CRC patients, pairing tumors with adjacent healthy tissues. The differential expression gene (DEG) analysis revealed apparently dysregulated metabolic programs,in what we focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2 genes which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potency of the Xc- system in a cellular setting, we applied a knowledge-based approach for analyzing gene perturbations from CRISPR screens across various cell types as well as using a variety of functional assays in five primary patient-derived organoid cell models to functionally verify our hypothesis. We identified a previously undescribed cell surface protein signature predicting chemotherapy resistance and further highlighted the causality and potential of pharmacological blockage of ferroptosis as promising avenue for cancer therapy. Biological processes such as redox homeostasis, ion/amino acid transporters and regulators of neuronal survival and differentiation were associated with these co-dependent genes in patient specimens. This study highlights a number of potential clinical targets for CRC and promotes patient-individual in vitro model systems as functionally validate in silico predictions.