Croner, R. S. | Search bioRxiv

bioRxiv2025

Patient-Specific Pharmacogenomics unveils xCT Regulation Pathways in Colon Cancer

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 and microRNA-seq analysis of tissue samples from 32 CRC, pairing tumors with adjacent healthy tissues. The differential expression gene (DEG) analysis revealed an interconnection between nutrients, metabolic programs, and cell cycle pathways. 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 de novo nucleotide synthesis were associated with these co-dependent genes in patient specimens. This study highlighted a number of overlooked genes as potential clinical targets for CRC and promotes stem cell-based, patient-individual in vitro model systems as a versatile partner platform to functionally validate in silico predictions, with focus on SLC7A11 and its associated genes in tumorigenesis.

cancer biology↗

bioRxiv2024

Transcription network of SLC7A11 (xCT) in colon cancer provides clinical targets for metabolic regulation and cell proliferation

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 in-depth comparative RNA-seq analysis of 32 CRC patients pairing tumor and healthy tissues (total of 73 samples). Strict thresholds for differential expression genes (DEG) analysis revealed an interconnection between nutrients, metabolic program, and cell cycle pathways. Among the upregulated DEGs, we focused on the Xc- system, composed of the proteins from SLC7A11 (xCT) and SLC3A2 genes, along with several interacting genes. To assess the oncogenic potency of the Xc- system in a cellular setting, we applied a knowledge-based approach, analyzing gene perturbations from CRISPR screens. The study focused on a set of 27 co-dependent genes that were strongly correlated with the fitness of SLC7A11 and SLC3A2 across many cell types. Alterations in these genes in 13 large-scale studies (e.g., by mutations and copy number variation) were found to enhance overall survival and progression-free survival in CRC patients. In agreement, the overexpression of these genes in cancer cells drives cancer progression by allowing effective management of the redox level, induction of stress response mechanisms, and most notably, enhanced activity of ion/amino acid transporters, and enzymes acting in de novo nucleotide synthesis. We also highlight the positive correlation between the Xc- system gene expression level, patient responsiveness to different chemotherapy treatments, and immune cell infiltration (e.g., myeloid-derived suppressor cells) in CRC tumors as a measure for their immunosuppressive activity. This study illustrates that knowledge-based interpretation by synthesizing multiple layers of data leads to functional and mechanistic insights into the role of SLC7A11 and its associated genes in CRC tumorigenesis and therapeutics.

cancer biology↗