Preventing breast cancer metastasis by killing tumor cells in their sleep

Breast Cancer Cells
Integrin-inhibiting drugs can make dormant breast cancer cells vulnerable to chemotherapy, Fred Hutch researchers found. (National Cancer Institute)

Oncology researchers have long believed that “dormant” breast cancer cells—those that have stopped dividing and are merely hiding out in the body—are unresponsive to chemotherapy. Yet those inactive cancer cells can wake up at any time and cause life-threatening metastases.

Scientists at the Fred Hutchinson Cancer Research Center say they’ve figured out how to prevent dormant breast cancer cells from ever waking up, and that the key is to disrupt a signaling system in blood vessels that protects the cells as they sleep. What’s more, they identified two compounds that can interrupt this protective signaling and cause the dormant cells to become responsive to chemotherapy. They published their findings in the journal Nature Cell Biology.

“It’s always been assumed that dormant cells cannot be killed by any kind of chemotherapy because they’re not dividing,” said Cyrus Ghajar, Ph.D., chief of the Laboratory for the Study of Metastatic Microenvironments at Fred Hutch, in an article posted on the center’s website. “But what we’re showing is that’s not true. They’re relying on survival signaling in their microenvironment, in this case specifically from blood vessels within the bone marrow. And if you can take away that signaling, you can sensitize them to chemotherapy.”

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Ghajar’s team focused on estrogen receptor-positive breast cancer, which recurs in an estimated 17% of patients who are diagnosed at the early stages of the disease. They set out to try to find a treatment that would prevent metastasis by attacking dormant tumor cells.

RELATED: Tackling triple-negative breast cancer by blocking 2 key survival pathways

So they took mouse models of breast cancer, gave them chemotherapy, and started searching for dormant cells in their bone marrow. They discovered that some sleeping cells were surrounded by tiny blood vessels and didn’t die when they were bombarded with chemotherapy. But the dormant cells that didn’t have blood vessels did respond to the chemo.

Then they studied both types of dormant cells, using RNA sequencing to look at genes that were active. They discovered that the dormant cells protected by blood vessels were rich with molecules that bind to proteins called integrins. So they started testing compounds that inhibit integrins until they hit on two that were effective at killing the dormant cells when combined with chemo.

“Chemo on its own would kill one third of all the single cells in our culture. But when we combined integrin inhibition and chemotherapy, we killed over 90% of the single cells in our cultures,” Ghajar said. He added that it wasn’t necessary for the cells to come out of their dormant state for them to become vulnerable to destruction.

The Fred Hutch research comes just two weeks after a team at Princeton published research suggesting that a protein called Tinagl1 inhibits the spread of triple-negative breast cancer in mouse models. They believe Tinagl1 works partly by inhibiting integrins. And just last week, a team in Switzerland described a method for using two FDA-approved drugs to transform early-stage breast cancer cells into fat cells, thereby preventing them from growing and spreading.

Even patients in the earliest stages of breast cancer face a risk of recurrence; dormant cancer cells have been found in the bone marrow of patients with stage 0 tumors. “Patients with breast cancer cells in the marrow recur more often than patients who don’t have cells in the bone marrow,” Ghajar said.

The next step for Ghajar’s team is to transform the integrin inhibitors used in the experiment into drugs that would be safe for people. He hopes to have compounds ready for human testing in three to five years.

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