Uncovering the lung cancer mechanisms through the chromosome structural ensemble characteristics and nucleation seeds

Abstract

Lung cancer is one of the most common cancers in humans. However, there is still a need to understand the underlying mechanisms of a normal cell developing into a cancer cell. Here, we develop the chromosome dynamic structural model and quantify the important characteristics of the chromosome structural ensemble of the normal lung cell and the lung cancer A549 cell. Our results demonstrate the essential relationship among the chromosome ensemble, the epigenetic marks, and the gene expressions, which suggests the linkage between chromosome structure and function. The analysis reveals that the lung cancer cell may have a higher level of relative ensemble fluctuation (micro CFI) and a higher degree of phase separation between the two compartments than the normal lung cell. In addition, the significant conformational "switching off" events (from compartment A to B) are more than the significant conformational "switching on" events during the lung cancerization. We identify "nucleation seeds" or hot spots in chromosomes, which initiate the transitions and determine the mechanisms. The hot spots and interaction network results reveal that the lung cancerization process (from normal lung to A549) and the reversion process have different mechanisms. These investigations have revealed the cell fate determination mechanism of the lung cancer process, which will be helpful for the further prevention and control of cancers.