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Ambeskovic, A.

Publications and source records attributed to Ambeskovic, A..

2 recordsLinked to original sources
bioRxiv2025

MYC and Epithelial to Mesenchymal Transition (EMT) Independently Predict Circadian Rhythm Disruption in Lung Adenocarcinoma

The molecular circadian clock is known to be disrupted in lung adenocarcinoma, and its disruption is pro-tumorigenic in mouse models of this disease. However, the determinants of disruption of the molecular clock in human cancer are not clear. We hypothesized that derangement in expression of specific circadian clock genes or elevated MYC expression could correlate with circadian disruption in human tumors, and used Clock Correlation Distance (CCD) to compare clock order and strength in tumors based on the expression of these genes. While the expression of individual circadian genes did not consistently correlate with disruption, tumors with the highest expression of MYC or high MYC pathway activation had significantly disrupted rhythms compared to those with lower MYC. Unexpectedly, a subset of tumors with very low levels of MYC, below that found in normal lung, also showed disruption of circadian rhythms, prompting us to explore novel determinants of disruption in these tumors. We found that expression of programs associated with epithelial to mesenchymal Transition (EMT) and TGF-{beta} signaling were enriched in tumors with the lowest MYC expression, and that, surprisingly, those tumors with a mesenchymal expression pattern had more ordered (stronger) rhythms. To directly test this correlation between cell state and rhythms, we exposed lung adenocarcinoma cells to TGF-{beta} to induce EMT. TGF-{beta} induced a quasi-mesenchymal phenotype and caused a significant increase in the amplitude of oscillations in these cells. Together, our data show that MYC expression, pathway activation, and a mesenchymal cell state are both independent determinants of circadian status in lung adenocarcinoma.

cancer biology↗
bioRxiv2020

Gene network modeling via TopNet reveals robust epistatic interactions between functionally diverse tumor critical mediator genes

Malignant cell transformation and the underlying genomic scale reprogramming of gene expression require cooperation of multiple oncogenic mutations. Notably, this cooperation is reflected in the synergistic regulation of downstream genes, so-called cooperation response genes (CRGs). CRGs impact diverse hallmark features of cancer cells and are not known to be functionally connected. Yet, they act as critical mediators of the cancer phenotype at an unexpectedly high frequency of >50%, as indicated by genetic perturbations. Here we demonstrate that CRGs function within a network of strong genetic interdependencies that are critical to the robustness of the malignant state. Our approach, termed TopNet, utilizes attractor-based ternary network modeling that takes the novel approach of incorporating uncertainty in the underlying gene perturbation data and is capable of identifying non-linear gene interactions. TopNet reveals topological gene network architecture that effectively predicts previously unknown, functionally relevant epistatic gene interactions, and thus, among a broad range of applications, has utility for identification of non-mutant targets for cancer intervention.

cancer biology↗