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Ohnmacht, A. J.

Publications and source records attributed to Ohnmacht, A. J..

3 recordsLinked to original sources

Enhancing Gene Expression Representation and Drug Response Prediction with Data Augmentation and Gene Emphasis

Representation learning for tumor gene expression (GEx) data with deep neural networks is limited by the large gene feature space and the scarcity of available clinical and preclinical data. The translation of the learned representation between these data sources is further hindered by inherent molecular differences. To address these challenges, we propose GExMix (Gene Expression Mixup), a data augmentation method, which extends the Mixup concept to generate training samples accounting for the imbalance in both data classes and data sources. We leverage the GExMix-augmented training set in encoder-decoder models to learn a GEx latent representation. Subsequently, we combine the learned representation with drug chemical features in a dual-objective enhanced gene-centric drug response prediction, i.e., reconstruction of GEx latent embeddings and drug response classification. This dual-objective design strategically prioritizes gene-centric information to enhance the final drug response prediction. We demonstrate that augmenting training samples improves the GEx representation, benefiting the gene-centric drug response prediction model. Our findings underscore the effectiveness of our proposed GExMix in enriching GEx data for deep neural networks. Moreover, our proposed gene-centricity further improves drug response prediction when translating preclinical to clinical datasets. This highlights the untapped potential of the proposed framework for GEx data analysis, paving the way toward precision medicine.

bioinformatics↗

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↗

The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity

Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analysed 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detected the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constituted drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduced anticipated associations, and in addition, we found that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.

cancer biology↗