Scientists discover key molecular differences between breast cancer cells in initial and metastatic tumors

By studying a deadly type of breast cancer called triple negative, Johns Hopkins Medicine scientists say they have identified key molecular differences between cancer cells that latch onto an initial tumor and those that venture out to form distant tumors.

Research, using mouse models and human tissue, could pave the way for the development of new treatments targeting these molecular variations.

A report on the results is published on August 3 in Science translational medicine.

“We have long needed new treatment targets and options for triple-negative breast cancers,” says Andrew Ewald, Ph.D., Virginia DeAcetis Professor of Basic Cancer Research and chair of the Department of Cell Biology at the Johns Hopkins University School of Medicine and co-lead of the Cancer Invasion and Metastasis program at the Johns Hopkins Kimmel Cancer Center. “These cancers often come back within three years of diagnosis, and treatments used for other breast cancers usually don’t work for triple negatives.”

An estimated 10-20% of the 280,000 breast cancers diagnosed in the United States each year are triple negative, and the rate is higher in African-American women, who are twice as likely as others to suffer from this condition. form of the disease.

The lethal nature of this type of cancer is marked by the fact that its cells lack molecular flags on its surface that connect to the hormones estrogen and progesterone and a cancer-promoting protein called Her2-neu. Many current breast cancer therapies work by targeting these flags, making them of little use to people with triple-negative tumors.

For the current study, the research team looked at the molecular differences between the initial or primary sites of triple-negative breast cancer and the areas where it has spread, or metastatic sites, among three different cell types: mouse models, human cancers implanted in mice, and primary and metastatic tissue samples taken from eight patients treated at Johns Hopkins Hospital.

The researchers used a combination of machine learning, cell imaging and biochemical analysis to identify differences in gene expression patterns of initial and metastatic tumors.

The bad news from our study is that cells from metastatic sites are super-optimized for migration and resistance to treatment. The good news is that we have identified several proteins called transcription factors that these cells need to meet the challenges of migration and thriving at metastatic sites, and we may be able to design new therapies that target these factors. of transcription. »


Andrew Ewald, Ph.D., Virginia DeAcetis Professor of Basic Cancer Research and Chair of the Department of Cell Biology at Johns Hopkins University School of Medicine

Specifically, Ewald and Johns Hopkins postdoctoral researcher Eloise Grasset, Ph.D., and other members of the research team discovered several unique properties in mouse cells engineered to have the mouse version of breast cancers. triple negatives and mice implanted with tumors. of people with triple negative breast cancer.

Scientists have found that when triple negative breast cancer cells invade other tissues on their way to another part of the body, they acquire two cellular properties: better movement and better survival.

To do this, breast cancer cells acquire a cell skeleton protein called vimentin, which improves the ability of so-called mesenchymal cells to migrate, a type of cell usually found in bones and bone marrow that moves around and makes new cells. .

Triple-negative breast cancer cells also gain survival benefits by producing a protein called E-cadherin, which is typically found in epithelial cells that line the ducts and linings of organs and frequently turn over.

When triple-negative breast cancer cells acquire such survival and migration qualities, scientists classify their cellular state as hybrid epithelial mesenchymal (EMT) cells.

To take a closer look at the molecules involved in EMT hybrid states, the scientists enlisted the help of Elana Fertig, Ph.D., division director and associate director of quantitative sciences and co-director of the Convergence Institute at the Johns Hopkins Kimmel Cancer Center, to track molecular patterns of single cells in cell-based assays that model primary tumor invasion and colony formation in a metastatic site.

Fertig’s computational team used machine learning techniques to find patterns among each cell’s expression of RNA, a cousin of DNA involved in protein production. Scientists found that most metastatic cells transformed into a more mobile and resistant hybrid EMT state. Ewald’s team then validated these states in samples from eight patients with triple-negative tumors, examining both primary tumors and tissue from metastatic sites from the same patients.

At the molecular level, the most metastatic cells have produced five proteins called transcription factors (Grhl2, Foxc2, Zeb1, Zeb2 and Ovol1) which promote the manufacture of proteins involved either in the invasion of cancer cells or in the formation of colonies. .

“The molecular differences between metastatic and primary tumors are likely the reason why metastatic tumor cells are so resistant to current treatments,” says Ewald.

His team is investigating ways to block transcription factor genes or their resultant proteins to halt the growth of metastatic cancer as well as whether the same molecular and cellular changes occur in other cancers, such as colon, adrenal , stomach and small intestine.

Source:

Journal reference:

Grasset, EM, et al. (2022) Metastasis from triple-negative breast cancer involves complex epithelial-mesenchymal transition dynamics and requires vimentin. Science translational medicine. doi.org/10.1126/scitranslmed.abn7571.

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