The approach of lung cancer treatment could promote the progression of the disease

Epigenetic regulators that modify the factors involved in gene switching are attractive anti-cancer targets, but will this strategy work? in vivo has not been proven yet. Studies on mice conducted by researchers led by a Boston Children's Hospital team now suggest that blocking an epigenetic regulator, a histone methyltransferase called G9a, that would represent a promising target for lung cancer would actually have the opposite effect and would increase the number of cancers. stem cells, or tumor propagating cells (TPCs) that drive cancer progression. Their studies also revealed that the inhibition of G9a-regulated G9a-regulated genes induced the formation of TPC in mice, resulting in a reduction in the number of lung tumors.

"People had looked at cell lines of lung tumors and had discovered that they were sensitive to G9a-inhibiting drugs," said Samuel Rowbotham, Ph.D., the first author of the paper published by researchers in Nature Communications. "In general, in tumor cell populations, these drugs would slow growth or even kill cells. But we found that these drugs also made the surviving tumor cells more related to the stem. We predicted that this would advance the disease and that is what we saw. "

The team's article titled "H3K9 Methyltransferases and Demethylases Control Cells That Spread in Lung Tumors and Progression of Lung Cancer".

Epigenetic regulators are proteins that modify chromatin or interact with chromatin and play a key role in managing the behavior of stem or progenitor cells and in defining the fate of cells, the authors explain. These proteins are often amplified, mutated or disrupted in cancer and play a key role in tumor development. G9a (Ehmt2) and Glp (Ehmt1) are histone methyltransferases (HMTs) that add methyl groups to histone H3 lysine 9 (H3K9) and are known to be involved in the regulation of embryonic stem cell differentiation. Studies have also linked G9a to cancer and the enzyme is mutated in various types of tumors. "The majority of studies describe G9a as an oncogene, concluding that G9a has pro-proliferative and pro-epithelial-mesenchymal (pro-EMT) transition functions," noted the team. "These results have stimulated the development of G9a / Glp chemical inhibitors in the hope that they could be used as anticancer drugs."

Studies by the Boston Children's Hospital team now suggest that blocking G9a may have the opposite effect expected and actually promote cancer growth. Early studies of adenocarcinoma cell lines showed that G9a treatment gave the cells an appearance more similar to the stem.

The team then transplanted cancer stem cells into mice and monitored the tumor growth. They found that animals receiving cells in which the G9a gene had been destroyed were more likely to develop lung tumors and metastases than animals receiving functional G9a cell transplants. Other studies have shown that the lack of G9a was associated with an increase in the number of CTPs. "These results suggest that G9a loss leads to progression of pulmonary adenocarcinoma and metastasis by increasing the proportion of TPC in the tumor," the researchers wrote.

G9a is not commonly mutated in human lung adenocarcinomas, but the team's analysis of data from hundreds of patients with adenocarcinoma revealed that a higher expression of G9a correlated with a much better 10-year survival. Interestingly, they also found that high levels of KDM3A expression, a lysine demethylase (KDM) that acts to demethylate H3K9, were associated with worse survival at 10 years.

When they then inhibited the KDM3A gene in mouse adenocarcinoma cells and transplanted them into mice, the animals developed fewer tumors than the control animals. Treatment of adenocarcinoma-positive mice with a KDM3A inhibitor also effectively reduced tumor growth compared to control mice, "suggesting that targeting of TPCs through the inhibition of KDM H3K9me might constitute a effective treatment of pulmonary adenocarcinoma ".

Although cancer stem cells have not yet been identified in human adenocarcinomas, Carla Kim, Ph.D., head of research, believes that the results deserve to be deepened, especially given evidence from a 2017 study suggesting that demethylase inhibitors could kill patients resistant to chemotherapy. cells from patients' tumors.

"Although we can not identify cancer stem cells in human patients, Dr. Rowbotham's work shows that you can start by studying a cancer stem cell in a mouse model and identify targets that may be clinically important," she said. she commented. "It shows the importance of finding the right molecule to which cancer is sensitive. In adenocarcinomas, a demethylase inhibitor is more likely to be more useful than an inhibitor of methyltransferase. "

The team is considering an adenocarcinoma treatment strategy that would initially target most of the cancer cells, and then use a treatment aimed specifically at cancer stem cells.

"Our data suggest that downregulation of G9a favors CPTs, leading to disease progression, metastasis, and poorer clinical outcomes, prompting the use of G9a inhibitors, particularly for the treatment of lung cancer, "the authors concluded. "In studying the epigenetic dependencies of CPTs, which represent a minority of tumor cells, our work has revealed a new potential therapeutic intervention for advanced lung cancer."

They suggest that their results contradict those of previous studies, perhaps because previous work was done primarily in cell lines. "Previous studies have not found the presence of cancer stem cells, and they're more numerous when you're dealing with these drugs," said Dr. Kim. "Because they represent only a small fraction of the tumor, everything about them can easily be omitted."

The results also highlight the importance of choosing the best cell models when looking for new cancer treatments, the researchers continued. "Studies based primarily on cell lines or whole tumors have suggested that G9a is oncogenic and a good target for epigenetic therapy, but our approach of analyzing different tumor populations has led to a surprisingly different conclusion. We propose that analyzing the effects of new therapies on different tumor populations, particularly the most tumorigenic stem cells, would be greatly beneficial. This could increase the success rate of clinical trials and thus reduce the cost and time needed to bring new cancer therapies to the patient. "