JAN 19, 2023 11:10 AM PST

Revealing the Molecules Underlying Metastasis

WRITTEN BY: Carmen Leitch

Cancer is at its deadliest when it metastasizes - when cancer cells break away from a tumor and migrate to other tissues, triggering cancer in a new location. Some studies have suggested that in some cancers, like melanoma, fewer than 0.1 percent of tumor cells metastasize. But metastasis has been blamed for 90 percent of cancer deaths. As such, scientists have been trying to determine the causes of metastasis; an understanding of the process could lead to new approaches to stop the deadly process. New research has identified two molecules that seem to promote the formation of new tumors in a mouse model of breast cancer, and the mechanisms used by those molecules. The findings have been reported in Developmental Cell.

Image credit: Pixabay

Previous research has shown that cancer cells are best at metastasizing to form new tumors when the cells are in the so-called quasi-mesenchymal (qM) state. This study has revealed that ΔNp63 and p73, which regulate the activity of other genes, help maintain the qM state in cancer cells.

Cells start the epithelial-mesenchymal transition (EMT), a process normally seen in development that is harnessed by cancer, in order to enter the qM state. As cells go from epithelial to more mesenchymal states, they become more aggressive and mobile. In the qM state, cells have not fully completed EMT; they become partly mesenchymal. Metastasis prefers this midpoint, because once cells are fully epithelial or fully mesenchymal, they don't metastasize.

After analyzing gene regulation in cancer stem cells the researchers zeroed in on two transcription factors, which help control the expression of other genes. One called ΔNp63 seems to have a direct influence on the ability of cancer stem cells to maintain a qM state. The other, called p73 can activate ΔNp63, so it has a similar effect.

If either ΔNp63 or p73 was inactivated in cancer stem cells, they transitioned to the end of the EMT spectrum, and were no longer able to metastasize.

The researchers also determined that in cancer stem cells, the researchers were surprised to find that ΔNp63 was not behaving as it does in healthy breast cells, and was instead influencing genes that affect wound healing and regeneration. For example, ΔNp63 triggers EGFR signaling, which promotes rapid cell growth during wound healing.

While unexpected, this finding "makes a lot of sense because the process of metastasis requires active proliferation. Metastatic cancer cells need both the properties of stem cells, such as the ability to self-renew and differentiate into different cell types, and the ability to multiply their numbers to grow new tumors," said first study author Arthur Lambert, PhD, a former Whitehead postdoc who is now an associate director of translational medicine at AstraZeneca.

This study may show why metastasis is so easy for qM cells; because only cells in the qM state can activate EGFR signaling powerfully enough to cause their own growth. The researchers are hopeful that these findings will eventually aid in the development of new metastasis-preventing therapies. They are continuing to investigate ΔNp63 function.

Sources: Whitehead Institute for Biomedical Research, Developmental Cell

About the Author
Bachelor's (BA/BS/Other)
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
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