Cell cycle pathways inhibit oral cancer metastasis

Researchers at Tokyo Medical and Dental University (TMDU) have discovered an important molecular mechanism that may help prevent oral cancer tumors from spreading throughout the body

The process of metastasis is when cancer cells gain vitality and spread to other parts
of the body.
Because this is one of the leading causes of cancer-related death, researchers are working to develop treatment strategies
that can stop metastasis.
In a recent publication in Cell Reports Tokyo Medical and Dental University (TMDU), a team led by researchers describes how a cell signaling molecule called transforming growth factor β (TGF-β) helps oral cancer cells gain this dangerous dynamics
.

Epithelial-mesenchymal transition (EMT) occurs when cancer cells acquire more stem-cell-like and aggressive properties under the induction of multiple signals and stimuli in the tumor microenvironment
.
The team focused on the signaling molecule TGF-β because its reported effects seemed contradictory: TGF-β can induce EMT in cancer cells, but also appears to prevent cancer cells from proliferating
by keeping them in the early stages of the cell division cycle, known as G1.
Therefore, the researchers aim to characterize the molecular details
of these mechanisms at the single-cell level.

Kazuki Takahashi, first author of the study, said: "It is not entirely clear whether tumor cells stimulated by TGF-β can both induce EMT and inhibit the cell cycle
.
Single-cell analysis will help us understand if these events occur in
different cell populations.
”

To verify this, the team used specially engineered versions of oral cancer cells that fluoresce red when they are in the G1 phase and green when
they are in any other cell cycle stage.
After TGF-β treatment, the number of red blood cells increased, indicating G1 phase cell increase
.
When examining the response of cell migration to TGF-β, most migrating cells also exhibited G1 blockade, indicating a correlation
between the two phenotypes.

"We then used single-cell RNA sequencing technology to detect gene expression in individual oral cancer cells treated with TGF-β," explains
Tetsuro Watabe, senior author of the paper.
"Interestingly, these experiments show that TGF-β can induce EMT
in these cells through two different pathways.
"

Cells that show G1 phase arrest in EMT are different from
cells that are not.
Further studies showed that these cells were associated with the expression of keratin-associated protein 2-3 (KRTAP2-3), which was also observed
in migrating cells.

Katarzyna Podyma-Inoue, first author of the study, said: "Survival analysis showed that patients with head and neck squamous cell carcinoma with high KRTAP2-3 levels had poorer overall survival, suggesting that KRTAP2-3 is a prognostic biomarker for this cancer
.
"

Together, these data provide important molecular details
about the complex nature of TGF-β in oral cancer cells.
By revealing these mechanisms through single-cell analysis, this study provides important information that will help develop therapies
that target metastasis.

TGF-β generates a population of cancer cells residing in G1 phase with high motility and metastatic potential via KRTAP2-3