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Notre Dame researchers find certain brain cells promote metastasis in breast cancer patients

| Thursday, November 5, 2020

As Breast Cancer Awareness Month drew to a close, the journal “Cell” published research spearheaded by Notre Dame scientists outlining new ways to think about breast cancer metastasis to the brain and its treatment.

The researchers found that a certain type of myeloid cells, located in the brain, can suppress this organ’s immune response and thus allow cancer to metastasize in breast cancer patients and survivors.

“Patients rarely die from primary breast cancer. Patients usually die from the metastatic cancer in the lung, in the bone, in the brain [that’s] difficult to treat,” Siyuan Zhang, one of the researchers, said.

He is an associate professor of biological sciences at Notre Dame and a researcher for the Harper Cancer Research Institute.

The paper’s big question, Zhang added, explored how to prevent tumor cells in breast cancer patients from spreading to and growing in the brain.

Through single-cell sequencing, the researchers were able to determine that a type of myeloid cells called microglia, which normally serve to inhibit brain inflammation — an immune response — wrap around cancerous cells to create an immunosuppressive environment, Zhang said.

This makes it so that “[the] body’s immune system cannot see the tumor cells anymore,” he said. And that invisibility ultimately lets the cancerous cells proliferate in the brain, effectively allowing primary breast tumors to metastasize.

Courtesy of Siyuan Zhang

An artistic rendition of the data obtained in the study uses color to quantify the relative distance between the brain’s microglia, a type of myeloid cell that inhibit brain inflammation.

“So what we were seeing was the microglia, expressing VISTA, would engage with the T cells, basically turning them off and then allowing cancer to continue to outgrow,” Ian Guldner, the research paper’s main author, said.

T cells tend to eradicate tumor cells; however, the researchers found that V-domain Ig suppressor of T cell activation (VISTA) proteins — which tend to bind to and deactivate these types of cells — were actually facilitating metastasis.

“If you give a patient — or in our case, a mouse — an antibody against VISTA, it will bind to … and block this protein from engaging its receptor on other cells,” Guldner said. This means that anti-VISTA blockers can treat cancer metastasis in the brain.

The research paper was a main part of Guldner’s doctoral dissertation when he worked in Zhang’s lab. After seven years of pursuing a PhD at Notre Dame, he left last week for his postdoctoral fellowship at Stanford University.

Zhang referred to the so-called seed and soil hypothesis, according to which metastatic cancerous cells, like seeds and weeds, will proliferate to other parts of the body where the environment is favorable, like fertile soil.

As the microglia “shield” the cancerous cells that make their way into the brain, Zhang explained, they essentially provide that favorable environment the cancer needs to thrive and metastasize.

“Currently, most of the cancer treatment is focused on the tumor cell per se, focused on the seed,” he said. “But our study has opened up though another way you can target the so-called environment or condition of the soil. That will give you an equally effective, if not more effective treatment.”

While the research used a transgenic mouse model, this was then translated to consider how the findings might be useful in human patients. The anti-VISTA antibody offers hopes for a clinical trial; however, more work is needed to ensure this can be carried out safely.

“These findings are a translatable method to the clinic,” Guldner said. “There’s still a long way to go.”

The anti-VISTA antibody “hasn’t been used in the brain context or brain metastases context yet when it comes to cancer, but it is something that could potentially one day work in humans,” he added.

This study is also significant because, as Guldner put it, “when we started it, the immune system in the brain wasn’t really well-studied.”

Besides offering new avenues for treating breast cancer to brain metastasis, their research also encourages the study of many other types and subtypes of brain cells, such as T cells, through single-cell sequencing.

“Our study really just used single-cell [sequencing] to reveal those so very complicated brain immune regulations,” Zhang said. “It is really just the tip of the iceberg.”

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About Adriana Perez

Adriana is a junior from Guayaquil, Ecuador majoring in Political Science and minoring in Journalism, Ethics and Democracy and Sustainability. You can find her on Twitter @adrianamperezr.

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