Scientists from Far Eastern Federal University (FEFU, Russia), University of Geneva (Switzerland), Minjiang University, and Fuzhou University (China) pointed out WDR74 protein playing an important role in lung cancer and melanoma primary tumors/metastases progression. During the research, the artificially gained WDR74 function brought about a high activity in cancer cells. However, when the function had been dropped cells failed to metastasize becoming more vulnerable to chemotherapy. Related articles are published in Cancer Letters and Oncogene.
Except for brain cancer and some forms of blood cancer, not the main tumor but its metastases kill the patient taking over vital organs.
Metastases form at a certain stage of the primary tumor progression when its cells start separating and entering the bloodstream. Such cells are called circulating tumor cells, and they give rise to metastases which are secondary tumors appearing in different parts of the human body.
Fortunately, just subtle minority, tenths or even hundredths of a percent, of circulating tumor cells is capable of metastasizing. A few years ago, Chinese scientists from the laboratory of Dr. Lee Jia (Fuzhou University) wondered what discriminates "successful" circulating tumor cells from "unsuccessful" ones. Searching for a possible answer, they analyzed tumor cells (proteomic analysis) and spotted proteins highly expressed in active metastatic cells and lost in passive ones. One of these proteins was WDR74; its expression level in "successful" circulating tumor cells was two times higher than in the initial tumor. Scientists set up hypotheses stated this protein is a trigger helping a circulating tumor cell turn into a secondary tumor.
"Within this discovery, two of our scientific publications were being built, one devoted to lung cancer, and the other to melanoma. To test the oncogenic activity of WDR74 in circulating tumor cells of lung cancer and melanoma, we "turned off" this protein by the method of gene correction CRISPR / Cas9 and interfering RNAs to remove/reduce the amount of protein. After that, we monitored what happens to the cells in the context of their proliferation, colony formation, cell cycle, ability to migrate and grasp in body tissues. We have also conducted the opposite experiment increasing the amount of WDR74 protein in cancer cells. Both types of experiment confirmed that WDR74 plays a crucial role in the progression of the tumor and its metastases. Protein absence decreases, and the presence increases the oncogenic properties of circulating tumor cells. In vivo this confirmed during the experiments conducted on mice." said prof. Vladimir Katanaev, one of the research authors, Head of the Laboratory of Pharmacology of Natural Compounds, Department of Pharmacology and Pharmacy of the FEFU School of Biomedicine.
The scientist explained that WDR74 has at least two mechanisms of action. In different tumors, they have different priorities. In lung cancer cells, the protein primarily regulates WNT signaling pathways, which are active in tumor cells and passive in healthy cells of our body. In melanoma, WDR74 indirectly affects the expression of a number of other proteins, including the famous p53. The sequence is as follows: WDR74 regulates the amount of ribosomal protein RLP5, which has additional, extraribosomal properties; RLP5 regulates MDM2 protein ligase, and MDM2, in turn, leads to the degradation of p53 protein. The question of which mechanism is responsible for the expression of WDR74 itself remains unsolved.
Lung cancer is notorious for the lack of effective therapy methods. The same is melanoma: the mechanisms of its progression understood poorly. The published studies open up new paths to the development of effective curing methods for metastases of these two cancer types with targeted drugs. Such remedies should hit specific protein targets in the circulating tumor cells. The drugs development is the task of the next stage of the work of scientists from Russia, China, and Switzerland or other research groups.
In 2020, the laboratory of prof. Vladimir Katanaev and the team of Dr. Lee Jia started joint research to develop new drugs for obliterating circulating tumor cells of triple-negative breast cancer. Scientists are after DNA aptamers (analogs of antibodies, but synthesized using DNA chains) that will neutralize protein targets FZD7 and EpCAM. The work became possible thanks to a co-granting program from the Russian Federal Property Fund (19-515-55013) and National Natural Science Foundation of China.
The present research papers were supported by grants from the National Natural Science Foundation of China (U1505225, 81773063, 81273548, 81961138017) and the Ministry of Science and Technology of China (2015CB931804).
WDR74 induces nuclear β-catenin accumulation and activates Wnt-responsive genes to promote lung cancer growth and metastasis, https://doi.org/10.1016/j.canlet.2019.12.011
WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5 - MDM2 - p53 pathway, https://doi.org/10.1038/s41388-020-1179-6