Biology subjects

Stange, D. E.

Publications and source records attributed to Stange, D. E..

4 recordsLinked to original sources

bioRxiv2026

Loss of UBP1 drives oxaliplatin resistance through a targetable dependency on translation initiation

Oxaliplatin is a common component of various chemotherapeutic regimens for the treatment of gastrointestinal cancers. However, the majority of patients exhibit resistance to oxaliplatin-based therapy. Here, we integrated knockout and transcription-activation CRISPR screens in patient-derived gastric cancer organoids (GC PDOs) to comprehensively profile major genetic and transcriptomic changes observed over the course of resistance acquisition. Our screens identified UBP1, a transcription factor frequently lost in GC, as a critical determinant of oxaliplatin resistance development. Leveraging a large GC organoid biobank from a co-clinical trial and primary tumor omics data, we reveal that downregulation of specifically MYC-driven ribosome biogenesis drives oxaliplatin resistance, highlighting the drugs role as a ribosome biogenesis stressor. Mechanistically, UBP1 loss reduced expression of its direct target, MAX, a MYC cofactor, leading to downregulation of ribosome biogenesis and protection against nucleolar stress. Crucially, we discover that such downregulation is inevitably followed by a compensatory reliance on translation initiation, making it a therapeutic vulnerability in oxaliplatin-resistant tumors. Consequently, the resistance could be overcome by a synergistic action of the translation initiation repressor 4EGI, and the effect was also maintained in PDO that acquired resistance in vivo under clinically relevant conditions. Our data uncover a common marker of oxaliplatin resistance and identify a novel therapeutic strategy to reverse resistance to one of the most frequently used anticancer drugs.

cancer biology↗

bioRxiv2026

Systematic functional drug testing in patient-derived models reveals ex vivo sensitivities associated with clinical outcome in rare solid tumors

Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling was performed within clinically relevant timelines across models from 126 patients with rare advanced solid tumors. Drug responses were consistent between model types. In most samples, we identified at least one potentially active compound, supporting feasibility at biopsy-scale. High in vitro sensitivity was associated with clinical benefit and progression-free survival. These findings support functional drug sensitivity testing as a complementary component in precision oncology for adults with rare cancers. Statement of SignificanceThis study presents a biopsy-compatible drug sensitivity testing platform for phenotype-based therapy stratification in rare cancers. It identifies actionable ex vivo drug responses and shows associations with clinical outcome in patients treated with screened therapies. These findings support functional testing as a complementary additional layer of stratification for therapeutic prioritization.

cancer biology↗

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↗

bioRxiv2023

Acquired epithelial WNT secretion drives niche independence of developing gastric cancer

Recent studies have shed light on the signaling pathways required for gastric tissue maintenance and how aberrations in these key pathways lead to gastric cancer development. Although it has been shown that the WNT pathway is important for gastric epithelial homeostasis, the identity and source of the responsible canonical WNT ligands remain unknown. Furthermore, it is unclear how gastric cancer acquires WNT niche independence - an important early step in tumorigenesis. Using human and mouse gastric organoids and in vivo mouse models, we found that mesenchymal WNT2B and WNT7B maintain gastric epithelium in homeostasis. Next, mouse genetic studies and single-cell multi-omics analyses revealed that activation of MAPK signaling induces secretion of WNT7B in the epithelium itself. We further confirmed that in human gastric cancer, MAPK pathway activation through HER2 overexpression or copy number gains of WNT2 confers WNT independence. Importantly, the epithelium-intrinsic WNT expression could be therapeutically inhibited. Taken together, our results reveal that normal gastric epithelial turnover relies on WNT ligands secreted by niche mesenchymal cells, while transformation involves acquisition of a WNT secretory phenotype in the epithelium - representing a potential target for therapeutic interventions.

cancer biology↗