Biology subjects

Mambetsariev, I.

Publications and source records attributed to Mambetsariev, I..

4 recordsLinked to original sources

bioRxiv2024

DNA walk of specific fused oncogenes exhibit distinct fractal geometric characteristics in nucleotide patterns

Background/ObjectivesThe complex system of cancer has led to an emphasis on understanding the more general causal relationship within the disease. In this context, concepts of symmetry and symmetry-breaking in distinct biological cell features or components have been examined as an approach to cancer investigation. However, there can be possible limitations in directly interpreting the symmetry-based approach from a physical viewpoint due to the lack of understanding of physical laws governing symmetry in complex systems like cancer. MethodsFractal geometry and DNA walk representation were employed to investigate the geometric features i.e., self-similarity and heterogeneity in DNA nucleotide coding sequences of wild-type and mutated oncogenes, tumour-suppressor, and other unclassified genes. The mutation-facilitated self-similar and heterogenous features were quantified by the fractal dimension and lacunarity coefficient measures, respectively. Additionally, the geometrical orderedness and disorderedness in the analyzed sequences were interpreted from the combination of the fractal measures. ResultsThe findings showed distinct fractal geometric features in the case of fusion mutations. It also highlights the possible interpretation of the observed fractal features as geometric analogues concerning explicit observations corresponding to specific cancer types. In addition, the two-dimensional multi-fractal analysis highlighted the presence of a single exponent in the scaling of mutation-mediated gene sequence self-similarity/complexity and heterogeneity. ConclusionsThe approach identified mutation-induced geometric features in gene sequences, demonstrating the potential of DNA walks and fractal analysis in translational research regarding cancer. The findings suggest that investigating fractal parameters can capture unique geometric features in nucleotide sequences, contributing to the understanding of cancers molecular complexity.

bioinformatics↗

bioRxiv2020

The Ephrin receptor A2 and Roundabout Guidance Receptor 1 heterodimer: A potential theranostic for squamous cell carcinomas

Squamous cell carcinomas (SCC) of the lung (LSCC) and head and neck (HNSCC) are very prevalent with poor prognosis and limited treatment options. In both cancer types, Ephrin receptor A2 (EPHA2) is known to be overexpressed and exhibit opposing effects via two distinct signaling mechanisms. While it can inhibit cancer cell survival and migration by ligand-dependent signaling through tyrosine kinase phosphorylation at Y588 and Y772, it can promote tumor progression and cell migration in a ligand-independent manner via phosphorylation at S897. Variable ABnormal morphology (VAB-1) is the C. elegans ortholog of the human ephrin receptor (EPHR) that interacts genetically and biochemically in a dose-dependent manner with the axon guidance receptor, SAX3, the worm ortholog of ROBO. Double mutants of vab-1(EPHR)/sx-3(ROBO) are synthetic lethal, underscoring the interaction between the two signaling pathways which prompted us to investigate their role in SCC. Using biochemical and biophysical techniques, we show that EPHA2 and ROBO1 reside in the same complex and interact physically to form a functional heterodimer in LSCC and HNSCC. Furthermore, we show that treating squamous cells with the SLIT2, ligand of ROBO1, hinders phosphorylation of EPHA2 at S897, and thereby, attenuates cell proliferation. Interestingly, SLIT2 can interact with EPHA2 and attenuate the proliferation of cells that have low ROBO1 expression. Additionally, SLIT2 can act synergistically with the EPHA2 inhibitor, Ensartinib to attenuate cell growth in LSCC and HNSCC cells. Taken together, the data suggest that SLIT2 may serve as a novel therapeutic for LSCC and HNSCC. Here, we propose to stratify patients for treatment with SLIT2 and/or Ensartinib, based on their EPHA2 and ROBO1 expression levels in the diseased tissue. Thus 85% of LSCC cases can be treated with combination of SLIT2+Ensartinib and 55% of HNSCC cases can be treated with either SLIT2 or Ensartinib. Furthermore, EPHA2 and ROBO1 may represent novel theranostics in these two diseases. One sentence summaryHeterodimerization of EPHA2 and ROBO1 receptors attenuates growth of squamous cell carcinomas of the lung and head and neck.

cancer biology↗

bioRxiv2019

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Tumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXN in silico and attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatin-sensitive and resistant states in these cells. The data highlight an alternate, non-genetic, mechanism underlying chemoresistance in lung cancer.

cancer biology↗

bioRxiv2019

Phenotypic Switching of Naïve T cells to Immune-suppressive Treg-like Cells by Mutant KRAS

Oncogenic (mutant) Ras protein Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes uncontrolled proliferation, altered metabolism, and loss of genome integrity in a cell-intrinsic manner. Here, we demonstrate that CD4+ T cells when incubated with tumor-derived exosomes from mutant (MT) KRAS non-small cell lung cancer (NSCLC) cells, patient sera, or a mouse xenograft model, induce phenotypic conversion to FOXP3+ Treg-like cells that are immune-suppressive. Furthermore, transfecting T cells with MT KRAS cDNA alone induced phenotypic switching and mathematical modeling supported this conclusion. Single-cell sequencing identified the interferon pathway as the mechanism underlying the phenotypic switch. These observations highlight a novel cytokine-independent, cell-extrinsic role for KRAS in T cell phenotypic switching. Thus, targeting this new class of Tregs represents a unique therapeutic approach for NSCLC. Since KRAS is the most frequently mutated oncogene in a wide variety of cancers, the findings of this investigation are likely to be of broad interest and have a large scientific impact.

cancer biology↗