Biology subjects

Krappmann, D.

Publications and source records attributed to Krappmann, D..

4 recordsLinked to original sources

bioRxiv2025

Systematic identification of pan-cancer single-gene expression biomarkers in drug high-throughput screens

Precision oncology relies on molecular biomarkers to stratify patients into responders and non-responders to a given treatment. Although gene expression profiles have historically been explored for biomarker discovery, fewer studies investigated single-gene expression biomarkers. Additionally, many approaches are limited to cancer type-specific associations, which constrain statistical power. To address these limitations, we developed a regression-based framework that corrects for tissue-specific biases and enhances detection of pan-cancer single-gene expression biomarkers of drug sensitivity in cancer cell line high-throughput drug screens. Our method maintains predictive performance post-correction, and successfully recovers established biomarkers, such as SLFN11 expression for DNA damaging agents. Notably, we identified SPRY4 and NES expression as biomarkers of sensitivity for compounds targeting ERK/MAPK signaling (adjusted p-value=4.016x10- and 7.221x10-, respectively). This approach offers a scalable strategy for biomarker discovery and holds potential for translation to more complex biological models and patient-derived datasets. Ultimately, pan-cancer single-gene expression biomarkers may improve patient stratification and clinical outcomes in precision oncology.

cancer biology↗

bioRxiv2024

The pharmacogenomic assessment of molecular epithelial-mesenchymal transition signatures reveals drug susceptibilities in cancer cell lines

The epithelial-mesenchymal transition (EMT) is characterised by the loss of cell-cell adhesion and cell polarity, which is often exploited by cancer cells to adopt a motile, invasive and metastatic phenotype. Whilst EMT is often linked with cancer progression and therapy resistance, strategies for its selective targeting remain limited. In order to address this, we infer EMT states of cancer cell lines from their molecular signatures and use predictive and causal modelling to estimate the effect of EMT on drug susceptibility in high-throughput drug screens. For example, we show that EMT signatures in melanoma cells can predict favourable responses to the HSP90 inhibitor luminespib and demonstrate that epithelial-like melanoma cells can be sensitised to luminespib upon stimulation of EMT by TGF-{beta}. Thus, we provide an analysis that systematically yields a set of potent drugs by exploiting vulnerabilities of cancer cells undergoing EMT, which may pave the way for therapies to target these cells.

cancer biology↗

bioRxiv2023

A gut meta-interactome map reveals modulation of human immunity by microbiome effectors

The molecular mechanisms by which the gut microbiome influences human health remain largely unknown. Pseudomonadota is the third most abundant phylum in normal gut microbiomes. Several pathogens in this phylum can inject so-called virulence effector proteins into host cells. We report the identification of intact type 3 secretion systems (T3SS) in 5 - 20% of commensal Pseudomonadota in normal human gut microbiomes. To understand their functions, we experimentally generated a high-quality protein-protein meta-interactome map consisting of 1,263 interactions between 289 bacterial effectors and 430 human proteins. Effector targets are enriched for metabolic and immune functions and for genetic variation of microbiome-influenced traits including autoimmune diseases. We demonstrate that effectors modulate NF-{kappa}B signaling, cytokine secretion, and adhesion molecule expression. Finally, effectors are enriched in metagenomes of Crohns disease, but not ulcerative colitis patients pointing toward complex contributions to the etiology of inflammatory bowel diseases. Our results suggest that effector-host protein interactions are an important regulatory layer by which the microbiome impacts human health.

microbiology↗

bioRxiv2021

Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1

Alternative splicing is controlled by differential binding of trans-acting RNA binding proteins (RBPs) to cis-regulatory elements in intronic and exonic pre-mRNA regions 1-3. How secondary structure in the pre-mRNA transcripts affects recognition by RBPs and determines alternative exon usage is poorly understood. The MALT1 paracaspase is a key component of signaling pathways that mediate innate and adaptive immune responses 4. Alternative splicing of MALT1 exon7 is critical for controlling optimal T cell activation 5,6. Here, we demonstrate that processing of the MALT1 pre-mRNA depends on RNA structural elements that shield the 5 and 3 splice sites of the alternatively spliced exon7. By combining biochemical analyses with chemical probing and NMR we show that the RBPs hnRNP U and hnRNP L bind competitively and with comparable affinities to identical stem-loop RNA structures flanking the 5 and 3 splice sites of MALT1 exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L unwinds these RNA elements to facilitate recruitment of the essential splicing factor U2AF2 to promote exon7 inclusion. Our data represent a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.

biochemistry↗