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

Abstract

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.