A potential new drug target has been identified that could be used in new treatments for melanoma and lung cancer that could prevent metastasis progression. Both of these forms of cancer are difficult to treat, and their progression is poorly understood.
The international team of researchers from Far Eastern Federal University (FEFU) in Russia, the University of Geneva in Switzerland, and Minjiang University and Fuzhou University in China have discovered that the protein WDR74, plays a key role in the metastasis progression of lung cancer and melanoma primary tumors.
In the majority of cancers, it is not the primary tumor that kills patients but the spread of cancer to other organs. Treatments can focus on killing or removing the primary tumor, but once cancer has spread to other organs, treatment is far less effective.
Chinese researchers at Dr Lee Jia’s laboratory at Fuzhou University were studying how circulating cancer cells give rise to metastasis. Only a tiny percentage of circulating cancer cells give rise to metastases – just tenths or hundredths of a percent. The researchers performed a proteomic analysis of tumor cells to identify the differences between the cancer cells that give rise to metastases and those that do not. They discovered proteins that were highly expressed in metastatic cells that were expressed at much reduced levels in passive tumor cells. One of the proteins, WDR74, was found to be expressed at twice the level in metastatic cells than in the primary tumor. The researchers hypothesized that WDR74 played an important role in triggering metastasis.
The researchers found that mice with artificially elevated levels of the WDR74 protein exhibited high levels of cancer activity. The researchers switched off the WDR74 gene using the CRISPR-Cas9 gene editing tool and used interfering RNAs to reduce or remove the WDR74 protein from cells. The researchers then monitored proliferation, colony formation, cell cycle, and the ability of the cancer cells to migrate and take hold in body tissues. The researchers also conducted a study that increased the level of the WDR74 protein in cells and monitored the effects of elevated protein levels.
Both studies confirmed that the protein plays an important role in the metastasis of cancer. Lower levels of the protein decreased the oncogenic properties of cancer cells and the oncogenic properties of the cancer cells increased when the protein was present in higher levels.
The mechanism of action differs in melanoma and lung cancer as the protein plays a different role in each type of cancer. In lung cancer, the WDR74 protein regulates WNT signaling pathways that are passive in healthy cells and active in tumor cells. In melanoma, the WDR74 protein indirectly affects the expression of several other proteins, including the degradation of the protein, p53. What is not yet known is the mechanism that leads to the expression of the WDR74 protein.
The findings of the researchers could potentially allow a drug to be developed that could target the WDR74 protein and slow or stop metastasis in these often-deadly cancers. If a drug can be developed that targets the protein in circulating cancer cells, it could stop the cancer from spreading to other organs in the body.
You can read more about the research in the papers – WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5–MDM2–p53 pathway – which was recently published in Oncogene. DOI: 10.1038/s41388-020-1179-6 and – WDR74 induces nuclear β-catenin accumulation and activates Wnt-responsive genes to promote lung cancer growth and metastasis – which was published in the journal, Cancer Letters. DOI: 10.1016/j.canlet.2019.12.011