Researchers have shown the key role that a protein called Ran plays in the mobility of ovarian cancer cells


Did you know that 90% of cancer patients die from distant metastasis?

The latter occurs when cancer cells have the ability to move within the patient’s body and invade its healthy tissues.

In a study published in Nature Communications, researchers from the University of Montreal Hospital Research Centre (CRCHUM) have shown the key role that a protein called Ran plays in the mobility of ovarian cancer cells.

They demonstrated these cells cannot migrate from cancerous sites without the help of Ran.

Implicated in cancer development and survival, Ran is often referred to as a shuttle protein mostly supporting transport between the inside of a cell and its nucleus.

In ovarian cancer cells, the team of researchers, led by Dr. Anne-Marie Mes-Masson and Dr. Diane Provencher, showed Ran acts as a taxi to the cell membrane for another protein, RhoA, which is important in cell migration.

“In normal cells, RhoA can make its way directly to the cell membrane but in ovarian cancer cells it cannot. It has to link to Ran first in order to reach the cell membrane.

It really needs a ride,” said Mes-Masson, a researcher at the CRCHUM, professor at Université de Montréal and member of the Institute du cancer de Montréal.

“In our study, we showed that in cancer cells where we inhibit the action of Ran, RhoA gets broken down. Without RhoA, cancer cells lose then their ability to move, migrate and invade healthy tissues.”

Thanks to the vast expertise in biochemistry of the first author, Dr. Kossay Zaoui, the science team was able to explain at least in part why Ran is so important in a cancer cell.

In many cancers high expression of Ran is often associated with poor outcomes.

“We have previously demonstrated that Ran is a good therapeutic target.

Our study helps us understand when and in which cancer patients our approach might be most beneficial.

As healthy cells do not need Ran to move around, we can target the cancer cells without touching the healthy cells.

Based on our findings, it is probable that inhibiting Ran will also be a winning strategy in other cancers,” said Dr. Provencher, a researcher at CRCHUM, Head of the Division of Gynecology Oncology, professor at Université de Montréal and member of the Institute du cancer de Montréal.

Addicted to ran, ovarian cancer cells stop moving when deprived
Simultaneous protein labeling: Ran (pink) and tubulin (green) in ovarian cancer cells. The majority of Ran is found in the nucleus, but our study reveals that a portion of it is localized on the surface of cells inducing movement and invasion in ovarian cancer via its partner RhoA Credit: Euridice Carmona, CRCHUM

The researchers have already begun to develop small molecules that can inhibit Ran and are testing them in the preclinical models they have developed to show that they can slow or eliminate cancer development.

They hope one day that these new drugs will make their way into the clinic to be used to treat ovarian cancer patients.

The Importance of Our Biobank

For three decades, Drs. Provencher and Mes-Masson have collaborated to create the largest biobank of ovarian cancer specimens from women who have consented to participate in their research program.

They managed to develop and characterize cell lines from tumour tissues, and these cell lines were essential to conduct this work.

These cell lines are now used by ovarian cancer research groups worldwide to conduct ovarian cancer research.

The patient’s precious contribution to research is fuelling the type of new discoveries that both researchers hope will help cure this deadly disease.

According to the Canadian Cancer Society, 2,800 Canadian women were diagnosed with ovarian cancer in 2017 and 1,800 died from the disease.

It is the fifth leading cause of death in North America.

Scientists at the Ovarian Cancer Action Research Centre at Imperial College London have discovered a mechanism that deactivates ovarian cancer cells.

The findings, published in EMBO Reports, could lead to better treatments for women with ovarian cancer.

The research has found a new mechanism for a protein named OPCML. This protein is known as a tumour suppressor, as it prevents cells turning cancerous.

However OPCML is usually lost in cancer patients. Scientists have now found that when OPCML is put back into cancer cells, it cleverly deactivates a type of protein called AXL.

Previous research has shown the AXL protein accelerates the growth and spread of ovarian cancer cells. Clinical trials are already underway for treatments that block AXL, called AXL inhibitors.

But this new early stage research demonstrates potential for minimising treatment with AXL inhibitors, and in turn reducing side effects for women being treated for ovarian cancer.

When AXL becomes activated, it renders cancer cells more aggressive, increasing their ability to move and spread to other parts of the body.

However, it also reveals itself to OPCML, which then drags the bound molecules into a specific region of the cell where AXL is deactivated.

The research was funded by medical research charity Ovarian Cancer Action and carried out at the Ovarian Cancer Action Research Centre at Imperial College London.

The study, co-authored by Dr. Chiara Recchi and Professor Hani Gabra, found that since OPCML already blocks most of AXL, much less AXL inhibitor is required to deactivate the ovarian cancer cells.

Since inhibitors always present a certain degree of toxicity, if the dose of the inhibitor could be reduced, the patients should suffer fewer side effects.

The next stage is to develop OPCML as a therapeutic agent.

Since OPCML acts on the external part of the cells, delivering it on the surface of cancer cells could represent an efficient therapeutic strategy.

Also, OPCML is a “natural” protein present in most of the cells of our bodies, so it should have minimal toxicity.

New treatments

Dr. Chiara Recchi, lead author of the study from the Department of Surgery and Cancer at Imperial, said:

“Our results are really exciting because they reveal an unusual biological mechanism and shed light on the function of AXL, pointing us in the right direction to find a way to switch it off in cancer patients. In this context, OPCML has a tremendous potential as therapeutic.”

Dr. Jane Antony, Research Associate and first author of the study said: “This study will enable new treatment strategies to be designed to fight recurrent and aggressive ovarian cancer, for which there are currently limited treatment options.

AXL has always been a key player in cancer metastasis and these results reveal how these cancer drivers can be modulated by tumour suppressors such as OPCML.”

Professor Iain McNeish, Director of Ovarian Cancer Action Research Centre at Imperial, said: “At the Ovarian Cancer Action Research Centre, our aim is always to translate important scientific discoveries into new treatments for our patients. These exciting results reveal potential new mechanisms by which we can attack ovarian cancer.”

More information: Kossay Zaoui et al. Ran promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion, Nature Communications (2019). DOI: 10.1038/s41467-019-10570-w

Provided by University of Montreal


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