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25 Publications visible to you, out of a total of 25
Pan-cancer analysis of telomere maintenance mechanisms.

Abstract (Expand)

Telomeres, protective caps at chromosome ends, maintain genomic stability and control cell lifespan. Dysregulated telomere maintenance mechanisms (TMMs) are cancer hallmarks, enabling unchecked cell … proliferation. We conducted a pan-cancer evaluation of TMM using RNA sequencing data from The Cancer Genome Atlas for 33 different cancer types and analyzed the activities of telomerase-dependent (TEL) and alternative lengthening of telomeres (ALT) TMM pathways in detail. To further characterize the TMM profiles, we categorized the tumors based on their ALT and TEL TMM pathway activities into five major phenotypes: ALT (high) TEL (low), ALT (low) TEL (low), ALT (middle) TEL (middle), ALT (high) TEL (high), and ALT (low) TEL (high). These phenotypes refer to variations in telomere maintenance strategies, shedding light on the heterogeneous nature of telomere regulation in cancer. Moreover, we investigated the clinical implications of TMM phenotypes by examining their associations with clinical characteristics and patient outcomes. Specific TMM profiles were linked to specific survival patterns, emphasizing the potential of TMM profiling as a prognostic indicator and aiding in personalized cancer treatment strategies. Gene ontology analysis of the TMM phenotypes unveiled enriched biological processes associated with cell cycle regulation (both TEL and ALT), DNA replication (TEL), and chromosome dynamics (ALT) showing that telomere maintenance is tightly intertwined with cellular processes governing proliferation and genomic stability. Overall, our study provides an overview of the complexity of transcriptional regulation of telomere maintenance mechanisms in cancer.

Authors: M. Hakobyan, H. Binder, A. Arakelyan

Date Published: 2nd Jul 2024

Publication Type: Journal

Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells

Abstract (Expand)

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer … between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Authors: Munevver Cinar, Lourdes Martinez-Medina, Pavan K Puvvula, Arsen Arakelyan, Badri N Vardarajan, Neil Anthony, Ganji P Nagaraju, Dongkyoo Park, Lei Feng, Faith Sheff, Marina Mosunjac, Debra Saxe, Steven Flygare, Olatunji B Alese, Jonathan L Kaufman, Sagar Lonial, Juan M Sarmiento, Izidore S Lossos, Paula M Vertino, Jose A Lopez, Bassel El-Rayes, Leon Bernal-Mizrachi

Date Published: 23rd May 2024

Publication Type: Journal

PSF toolkit: an R package for pathway curation and topology-aware analysis.

Abstract (Expand)

Most high throughput genomic data analysis pipelines currently rely on over-representation or gene set enrichment analysis (ORA/GSEA) approaches for functional analysis. In contrast, topology-based … pathway analysis methods, which offer a more biologically informed perspective by incorporating interaction and topology information, have remained underutilized and inaccessible due to various limiting factors. These methods heavily rely on the quality of pathway topologies and often utilize predefined topologies from databases without assessing their correctness. To address these issues and make topology-aware pathway analysis more accessible and flexible, we introduce the PSF (Pathway Signal Flow) toolkit R package. Our toolkit integrates pathway curation and topology-based analysis, providing interactive and command-line tools that facilitate pathway importation, correction, and modification from diverse sources. This enables users to perform topology-based pathway signal flow analysis in both interactive and command-line modes. To showcase the toolkit's usability, we curated 36 KEGG signaling pathways and conducted several use-case studies, comparing our method with ORA and the topology-based signaling pathway impact analysis (SPIA) method. The results demonstrate that the algorithm can effectively identify ORA enriched pathways while providing more detailed branch-level information. Moreover, in contrast to the SPIA method, it offers the advantage of being cut-off free and less susceptible to the variability caused by selection thresholds. By combining pathway curation and topology-based analysis, the PSF toolkit enhances the quality, flexibility, and accessibility of topology-aware pathway analysis. Researchers can now easily import pathways from various sources, correct and modify them as needed, and perform detailed topology-based pathway signal flow analysis. In summary, our PSF toolkit offers an integrated solution that addresses the limitations of current topology-based pathway analysis methods. By providing interactive and command-line tools for pathway curation and topology-based analysis, we empower researchers to conduct comprehensive pathway analyses across a wide range of applications.

Authors: S. Hakobyan, A. Stepanyan, L. Nersisyan, H. Binder, A. Arakelyan

Date Published: 8th Sep 2023

Publication Type: Journal

PSF toolkit: an R package for pathway curation and topology-aware analysis

Abstract (Expand)

Most high throughput genomic data analysis pipelines currently rely on over-representation or gene set enrichment analysis (ORA/GSEA) approaches for functional analysis. In contrast, topology-based … pathway analysis methods, which offer a more biologically informed perspective by incorporating interaction and topology information, have remained underutilized and inaccessible due to various limiting factors. These methods heavily rely on the quality of pathway topologies and often utilize predefined topologies from databases without assessing their correctness. To address these issues and make topology-aware pathway analysis more accessible and flexible, we introduce the PSF (Pathway Signal Flow) toolkit R package. Our toolkit integrates pathway curation and topology-based analysis, providing interactive and command-line tools that facilitate pathway importation, correction, and modification from diverse sources. This enables users to perform topology-based pathway signal flow analysis in both interactive and command-line modes. To showcase the toolkit’s usability, we curated 36 KEGG signaling pathways and conducted several use-case studies, comparing our method with ORA and the topology-based signaling pathway impact analysis (SPIA) method. The results demonstrate that the algorithm can effectively identify ORA enriched pathways while providing more detailed branch-level information. Moreover, in contrast to the SPIA method, it offers the advantage of being cut-off free and less susceptible to the variability caused by selection thresholds. By combining pathway curation and topology-based analysis, the PSF toolkit enhances the quality, flexibility, and accessibility of topology-aware pathway analysis. Researchers can now easily import pathways from various sources, correct and modify them as needed, and perform detailed topology-based pathway signal flow analysis. In summary, our PSF toolkit offers an integrated solution that addresses the limitations of current topology-based pathway analysis methods. By providing interactive and command-line tools for pathway curation and topology-based analysis, we empower researchers to conduct comprehensive pathway analyses across a wide range of applications.

Authors: Siras Hakobyan, Ani Stepanyan, Lilit Nersisyan, Hans Binder, Arsen Arakelyan

Date Published: 23rd Aug 2023

Publication Type: Journal

Transcriptomic Maps of Colorectal Liver Metastasis: Machine Learning of Gene Activation Patterns and Epigenetic Trajectories in Support of Precision Medicine.

Abstract (Expand)

The molecular mechanisms of the liver metastasis of colorectal cancer (CRLM) remain poorly understood. Here, we applied machine learning and bioinformatics trajectory inference to analyze a gene … expression dataset of CRLM. We studied the co-regulation patterns at the gene level, the potential paths of tumor development, their functional context, and their prognostic relevance. Our analysis confirmed the subtyping of five liver metastasis subtypes (LMS). We provide gene-marker signatures for each LMS, and a comprehensive functional characterization that considers both the hallmarks of cancer and the tumor microenvironment. The ordering of CRLMs along a pseudotime-tree revealed a continuous shift in expression programs, suggesting a developmental relationship between the subtypes. Notably, trajectory inference and personalized analysis discovered a range of epigenetic states that shape and guide metastasis progression. By constructing prognostic maps that divided the expression landscape into regions associated with favorable and unfavorable prognoses, we derived a prognostic expression score. This was associated with critical processes such as epithelial-mesenchymal transition, treatment resistance, and immune evasion. These factors were associated with responses to neoadjuvant treatment and the formation of an immuno-suppressive, mesenchymal state. Our machine learning-based molecular profiling provides an in-depth characterization of CRLM heterogeneity with possible implications for treatment and personalized diagnostics.

Authors: O. Ashekyan, N. Shahbazyan, Y. Bareghamyan, A. Kudryavzeva, D. Mandel, M. Schmidt, H. Loeffler-Wirth, M. Uduman, D. Chand, D. Underwood, G. Armen, A. Arakelyan, L. Nersisyan, H. Binder

Date Published: 28th Jul 2023

Publication Type: Journal

Transcriptional states of CAR-T infusion relate to neurotoxicity – lessons from high-resolution single-cell SOM expression portraying

Abstract (Expand)

Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular … data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient's infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity. Keywords: CAR-T cell immunotherapy; bioinformatics workflow; data portraying; single-cell transcriptomics; transcriptional states. Copyright © 2022 Loeffler-Wirth, Rade, Arakelyan, Kreuz, Loeffler, Koehl, Reiche and Binder.

Authors: Henry Loeffler-Wirth, Michael Rade, Arsen Arakelyan, Markus Kreuz, Markus Loeffler, Ulrike Koehl, Kristin Reiche, Hans Binder

Date Published: 28th Sep 2022

Publication Type: Journal

Integrated Multi-Omics Maps of Lower-Grade Gliomas.

Abstract (Expand)

Multi-omics high-throughput technologies produce data sets which are not restricted to only one but consist of multiple omics modalities, often as patient-matched tumour specimens. The integrative … analysis of these omics modalities is essential to obtain a holistic view on the otherwise fragmented information hidden in this data. We present an intuitive method enabling the combined analysis of multi-omics data based on self-organizing maps machine learning. It "portrays" the expression, methylation and copy number variations (CNV) landscapes of each tumour using the same gene-centred coordinate system. It enables the visual evaluation and direct comparison of the different omics layers on a personalized basis. We applied this combined molecular portrayal to lower grade gliomas, a heterogeneous brain tumour entity. It classifies into a series of molecular subtypes defined by genetic key lesions, which associate with large-scale effects on DNA methylation and gene expression, and in final consequence, drive with cell fate decisions towards oligodendroglioma-, astrocytoma- and glioblastoma-like cancer cell lineages with different prognoses. Consensus modes of concerted changes of expression, methylation and CNV are governed by the degree of co-regulation within and between the omics layers. The method is not restricted to the triple-omics data used here. The similarity landscapes reflect partly independent effects of genetic lesions and DNA methylation with consequences for cancer hallmark characteristics such as proliferation, inflammation and blocked differentiation in a subtype specific fashion. It can be extended to integrate other omics features such as genetic mutation, protein expression data as well as extracting prognostic markers.

Authors: H. Binder, M. Schmidt, L. Hopp, S. Davitavyan, A. Arakelyan, H. Loeffler-Wirth

Date Published: 4th Jun 2022

Publication Type: Journal

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