Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data

Buzdin, Anton; Zhavoronkov, Alex; Korzinkin, Mikhail; Venkova, Larisa; Zenin, Aleksandr; Smirnov, Philip Yu.; Borisov, Nicolas

doi:10.3389/fgene.2014.00055

Cited by 85 publications

(144 citation statements)

References 22 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…In addition, the folding, sorting, and degradation pathway was activated, which is also known as unfolded protein response (UPR) or endoplasmic reticulum stress. Using the OncoFinder biomathematical method (25, 26), we were able to distinguish the activator and repressor role of every gene in each pathway of the gene expression data for individual samples (Table 3). Similar to KEGG findings, protein degradation pathways were activated by Alk4 down-regulation, whereas protein and glucose synthesis were inhibited leading to muscle wasting.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

et al. 2016

View full text Add to dashboard Cite

Skeletal muscle fibrosis and impaired muscle regeneration are major contributors to muscle wasting in Duchenne muscular dystrophy (DMD). Muscle growth is negatively regulated by myostatin (MSTN) and activins. Blockage of these pathways may improve muscle quality and function in DMD. Antisense oligonucleotides (AONs) were designed specifically to block the function of ALK4, a key receptor for the MSTN/activin pathway in skeletal muscle. AON-induced exon skipping resulted in specific Alk4 down-regulation, inhibition of MSTN activity, and increased myoblast differentiation in vitro. Unexpectedly, a marked decrease in muscle mass (10%) was found after Alk4 AON treatment in mdx mice. In line with in vitro results, muscle regeneration was stimulated, and muscle fiber size decreased markedly. Notably, when Alk4 was down-regulated in adult wild-type mice, muscle mass decreased even more. RNAseq analysis revealed dysregulated metabolic functions and signs of muscle atrophy. We conclude that ALK4 inhibition increases myogenesis but also regulates the tight balance of protein synthesis and degradation. Therefore, caution must be used when developing therapies that interfere with MSTN/activin pathways.—Pasteuning-Vuhman, S., Boertje-van der Meulen, J. W., van Putten, M., Overzier, M., ten Dijke, P., Kiełbasa, S. M., Arindrarto, W., Wolterbeek, R., Lezhnina, K. V., Ozerov, I. V., Aliper, A. M., Hoogaars, W. M., Aartsma-Rus, A., Loomans, C. J. M. New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The KEGG pathway gene sets were tested for association with the group variable using the R Bioconductor global test package (23, 24). In addition to the KEGG-based pathway analysis, the OncoFinder method was used (25, 26). We also identified biologic pathways and networks through Ingenuity Pathway Analysis (IPA; Qiagen, Redwood, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In multiple previous studies, OncoFinder was utilized to analyze human and non-human samples from a broad range of conditions including leukemia, solid cancers, fibrosis, age-related macular degeneration disease, asthma, Hutchinson-Gilford disease and cell culture [17–20]. The formula for PAS calculation for a given pathway ( p) is as follows:

P A S_{p} = false(true \sum_{n} A R R_{n p} \cdot lg (C N R_{n})) / N

[21]. The functional role of a gene product in a pathway is reflected here by a discrete flag activator/repressor role ( ARR ), which equals 1 for an activator, −1 for a repressor, and shows intermediate values −0,5; 0,5 and 0 for the gene products having intermediate repressor, activator, or unknown roles, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…We applied OncoFinder original algorithm [21] for functional annotation of the primary expression data and for calculating pathway activation strength (PAS) scores and cancer-to-normal ratios (CNRs). CNR n is the ratio of the expression levels of a gene n in the sample under investigation to the average expression in the control group of samples.…”

Section: Methodsmentioning

confidence: 99%

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Petrov

Suntsova

Mutorova

et al. 2016

Aging

View full text Add to dashboard Cite

Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

show abstract

“…Conveying the NGS gene-level data to the cellular signalling pathway level is key to predict functional consequences from transcriptomic profiling. However, most of the models cannot use data from multiple sequencing platforms, cannot efficiently handle the high-throughput quantification of pathway activation scores for individual biological samples required for clinical use and cannot meet the time frame needed for treatment of glioblastomas [67]. A method termed Oncofinder was recently developed for predicting target drug efficacy based on a patient's cancer-specific pattern of signalling pathway activation, particularly for pathways including molecular targets of respective drugs [68].…”

Section: Personalized Medicine Paradigm For the Treatment Of Brain Tumentioning

confidence: 99%

Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

Kalasauskas¹,

Renovanz²,

Bikar³

et al. 2017

J Carcinog Mutagen

View full text Add to dashboard Cite

Glioblastoma is the most common and most malignant type of intrinsic brain tumor in adults. The standard of care for glioblastoma consists of surgical debulking followed by combined radiochemotherapy. The clinical efficacy of standard therapies for newly diagnosed glioblastomas is rather modest with the highest survival rate at 5-years being less than 10%. Inevitable recurrence after cytotoxic therapies poses the major challenge in the clinical management of high grade gliomas. For recurrent glioblastomas, there is no standard therapy with lack of level one evidence for treatment efficacy. Recent evidence indicates that post-therapy recurrence in gliomas is a consequence of a plethora of molecular and cellular factors including intratumoural heterogeneity, functional hierarchy of distinct types of glioma cells, dynamic changes in the molecular landscapes and cellular composition of the tumour during therapy and the impact of particular treatment modalities. There is an emerging consensus that molecular distinctions within and between individual tumours is an important factor determining clinical outcomes. Consequently, integrated approaches based on the combination of molecular profiling with traditional methods such as immunohistochemical phenotyping, karyotyping and/or non-quantitative methylation-specific PCR have emerged as a promising venue towards increasing the predictive value of diagnostics for malignant brain tumors. The high level of inter-and intra-tumoural molecular diversity in gliomas underscores the need of integrating high throughput molecular profiling and pharmacogenomics into a diagnostic paradigm for gliomas and raises the possibility that molecular-instructed personalized treatments may provide clinical benefit to patients with glioblastoma, particularly in the setting of post-treatment recurrence. Here we discuss potential prospects and challenges of patient-tailored diagnostics and personalized treatment strategies for recurrent glioblastomas.

show abstract

Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data

Cited by 85 publications

References 22 publications

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

Contact Info

Product

Resources

About