Researchers have discovered a new gene interaction mechanism that leads to metastasis in cancer cells: pro-oncogenes MYC and TWIST1. Using a mouse model, scientists have found that when these two transcription factors interact in tumor cells, they create an environment that co-opts immune cells, and allows tumor cells to metastasis throughout the body using the host immune system. Furthermore, these researchers have discovered that blocking a key step in this genetic pathway can help prevent cancer from spreading throughout the body, an element of cancer that can lead to the death of the patient.
“Most cancer-related deaths are caused by metastasis, but there are currently no treatments available to stop it,” explains lead author Renumathy Dhanasekaran, a Ph.D. student at Stanford University. “The main goal of our research is to understand how cancer-causing genes enable metastasis and use that information to identify targeted therapies that may prevent it.”
Dhanasekaran and colleagues discovered that MYCand TWIST1, two transcription factors, together elicit a cytokinome (a set of cytokines which in this case include CcI2 and Il13), whose signaling enabled crosstalk between cancer cells and host macrophages. This molecular interaction was found to drive tumor progression.
While these new findings published in eLife may be based on animal models, the researchers did apply their findings to a cohort of cancer patients’ genomic data, and have found several similar correlations between genetic expression levels of MYC and TWIST1 and patient response to treatment, and aggressiveness of tumor cells. This data may help clinicians to identify cancer patients at high risk of having tumors metastasis, such as patients with large or inoperable tumors. These findings may also inform the development of new strategies to prevent or treat metastasis.
The methods Dhanasekaran and her colleagues used to discover this interaction were genetically engineered mice that expressed both MYC and TWIST1.They found that this combination led to increased metastases compared to control. They also saw that the cancer cells produced inflammation-promoting molecules Ccl2 and Il13, which attracted macrophages and elicited their recruitment and polarization. This interaction makes it easier for the cancer cells to migrate to new areas of the body.
The team next showed that exposing mice with liver cancer caused by MYCalone to Ccl2 and Il13 causes metastasis. However, blocking this specific combination of cytokines appeared to hinder the process.
To see if the two genes also contributed to metastases in humans, the scientists analyzed nearly 10,000 samples of tumors collected from humans with 33 different types of cancer. They found that patients whose tumors expressed MYC and TWIST1 correlated to poorer survival, higher levels of Ccl2 and Il13, and an increase in macrophages found to have infiltrated tumors. They also found that in patients with liver cancer, elevated levels of Il13 predicted invasive and aggressive of the cancer. Additionally, they found the combined inhibition of Ccl2 and Il13 profoundly impeded metastasis in the researchers’ in vivomodel of liver cancer.
This may suggest a new treatment possibility for liver cancer patients, as previous clinical trials where inhibition of Ccl2 alone was not effective in treating solid tumors.
“Interestingly, MYC and TWIST1 have previously been shown to cooperate in a positive way to modulate inflammation during embryonic development,” says senior author Dean Felsher, PhD, at Stanford University. “These microenvironment changes are needed to enable mesodermal cells to migrate to their destination. But in multiple human cancers, both MYCand TWIST1are over-expressed, and [our study] suggests that they in turn cause tumor invasion by ‘hijacking’ this embryonic cell migration program.”
The team of researchers also monitored Ccl2 and Il13 levels in 25 patients with liver cancer and 10 control patients with cirrhosis. They found that only the patients with liver cancer had elevated levels of the two molecules and, of this group, those with higher levels of Il13 were more likely to have aggressive tumors.
“These results suggest that patients with more aggressive cancers will likely have higher levels of Ccl2 and Il13 cytokines in their blood,” Felsher concludes. “Testing for these molecules in future could help identify those who may benefit from combination therapies that target them.”
While clinical trials have not yet been started, this discovery holds a great deal of promise for preventing metastasis in not only liver cancer, but multiple types of cancer, and an entirely new approach for treating patients with advanced forms of the disease.
