Biology subjects

Kahlert, U. D.

Publications and source records attributed to Kahlert, U. D..

3 recordsLinked to original sources

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↗

bioRxiv2021

Meta-analysis on reporting practices as a source of heterogeneity in in vitro cancer research

BackgroundHeterogeneity of results of exact same research experiments oppose a significant socio-economic burden. In vitro research presents the early step of basic science and drug development projects. Insufficient methodological reporting is likely to be one of the contributors to results heterogeneity, however, little knowledge on reporting habits of in vitro cancer research and their effects on results reproducibility is available. Glioblastoma is a form of brain cancer with largely unmet clinical need. MethodsHere we use systematic review to describe reporting practices in in vitro glioblastoma research using the U87-MG cell line and perform multilevel random-effects meta-analysis followed by meta-regression to explore sources of heterogeneity within that literature, and any associations between reporting characteristics and reported findings. ResultsIn 137 identified articles, the overall methodological reporting is disappointing, e.g., the control type, mediums glucose level and cell density are reported in only 36.5, 21.2 and 16.8 percent of the articles, respectively. After adjustments for different drug concentrations and treatment durations, a three-level meta-analysis proves meaningful results heterogeneity across the studies (I2 = 70.1%). ConclusionsOur results further support the ongoing efforts of establishing consensus reporting practices to elevate durability of results. By doing so, we hope that this work will raise awareness of how stricter reporting may help to improve the frequency of successful translation of preclinical results into human application, not only in neuro-oncology. FundingWe received no specific funding for this project.

cancer biology↗