Researchers discover that epigenetic status determines metastasis

Scientists from the German Cancer Research Center (DKFZ) and the University of Heidelberg studied the behavior of tumor cells spreading at the site of metastasis in mice. Some tumor cells immediately begin to metastasize. Others leave the blood vessel and may then enter a long period of dormancy. What determines the path cancer cells take is their epigenetic status. This was also confirmed by experiments on human tumor cells. The results of the study could pave the way for new diagnostic and therapeutic applications.

The work appears in Natural cancer.

What makes cancer so dangerous? Cancer cells that leave the primary tumor to reach distant sites in the body where they can develop into daughter tumors, called metastases. Although most primary tumors can be treated effectively, metastases pose the real danger. Oncologists estimate that more than 90% of all cancer deaths in solid tumors are due to metastases.

Researchers have worked for decades to understand and prevent the spread of tumor cells. However, the mechanisms that allow a cancer cell to survive in a distant organ and ultimately metastasize are still largely unknown.

To spread throughout the body, cancer cells travel through the blood and lymphatic systems. Scientists from DKFZ and the University of Heidelberg have developed a method to observe the behavior of migrating cancer cells in mice immediately after their arrival in the metastatic organ, in this case the lung.

The team led by the first two authors Moritz Jakab and Ki Hong Lee discovered that some tumor cells, once arriving in the metastatic organ, leave the blood vessel and enter a resting state. Other cancer cells begin to divide directly in the blood vessel and metastasize.

This delicate decision about the fate of metastasized tumor cells is controlled by the endothelial cells that line the interior of all blood vessels. They release factors from the Wnt signaling pathway that promote the exit of tumor cells from the blood vessel and thus trigger latency. When the researchers turned off the Wnt factors, the latency no longer occurred.

What distinguishes latent cancer cells from growing metastasized cancer cells?

“At this point, we asked ourselves the question: why do some cancer cells immediately metastasize, while others fall into a sort of dormancy?” said Moritz Jakab.

Dormant and metastasized cancer cells did not differ genetically or in many other molecular aspects. But the researchers were able to detect a subtle difference: DNA methylation differed between the two cell types. Tumor cells, whose DNA was less methylated, responded sensitively to Wnt factors, leading to blood vessel extravasation and subsequent latency. In contrast, the most methylated cancer cells did not respond to Wnt factors, remained in the blood vessel, and immediately began metastatic growth.

To test this hypothesis, the team examined the DNA methylation status of various tumor cell lines. Indeed, they found that this was directly correlated with their metastatic potential.

“These results are surprising and could have considerable consequences for the diagnosis and treatment of tumors. The study results could, for example, help to use certain methylation patterns as biomarkers to predict to patients the importance of the burden of dormant cancer cells”, and thus, how likely is the patient to relapse after successful treatment of the primary tumor”, explains lead author Hellmut Augustin. “But we first need to study whether natural human tumors behave the same as the cell lines used or experimental tumors.”