Metastatic breast cancer invades lung tissue. Image Credit: Gertler Lab, Koch Institute (CC BY-NC-SA 2.0)
Nearly all cancers have the potential to spread to other parts of the body. Their ability to metastasize via tissues and blood or lymph vessels depends on several factors, such as the type, size, and location of the primary tumor. But metastasis is not a random process, and tumor cells often exhibit a preference for colonizing specific organs – a phenomenon also known as organotropism. In the case of breast cancer, these preferred sites are the lungs, liver, brain, and bones.
The mechanisms by which cells survive in a new, drastically different tissue environment remain poorly understood. One theory is that the structure of chromosomes inside cells, which plays a determining role in cell function and identity, may explain how tumors adapt to different tissues.
Das et al. used a new genome-folding-centric approach to find out why breast cancer metastasizes to certain organs, such as the lung. The researchers analyzed genome compartmentalization data of various human cancer cell lines, including breast cells (both localized cancer and lung-metastatic cancer cells) and lung cells (healthy and cancerous ones).
The results showed that the three-dimensional arrangement of DNA within the cell nucleus might play a role in a tumor’s metastatic behavior. One aspect of genome structure is that the way in which long DNA strands are packed and folded inside the human nucleus is not random. Chromosome regions are spatially separated into two compartments: one active, containing genes that are available to be transcribed or used, and another inactive, where genes are tightly packed and silent. As cancer cells become invasive and enter a migratory state, specific parts of the genome switch between these compartments. This spatial reorganization influences gene accessibility and impacts the preference for metastatic sites. The most significant finding is that lung-metastatic breast cancer cells acquire a genome architecture that structurally resembles features of normal lung cells. Further, these changes in compartment identity are not always accompanied by increases in gene transcription. The study by Das et al. contributes to a broader understanding of how the three-dimensional genome may contribute to metastatic transformation of cancerous cells and their ability to colonize distant sites. It also highlights that certain genome compartmentalization signatures might be used as a prognostic biomarker. However, significant work in translational and clinical research would be required before these benefits could be realized. The next critical step is to validate these genome changes and their role in organotropism in patient-derived samples. Further studies are also needed to identify the specific mechanisms that regulate and control the compartment switches.
