Postdoctoral associate Danhui Ma (left) spent countless hours learning new microscopy techniques under the guidance of Dorothy Sipkins to confirm how breast cancer spreads to the leptomeninges (membranes that protect the brain and spinal cord).
How Breast Cancer Spreads to the Brain
Published
Once cancer gets inside the inner membranes that protect the brain and spinal cord (the leptomeninges), the disease can circulate in the cerebrospinal fluid and spread throughout the central nervous system. The outcome for patients is devastating, with a median survival time of less than six months.
That’s why clinician-scientist Dorothy Sipkins, MD, PhD, and her team at Duke University School of Medicine have kept pushing for nearly 10 years to find out how cancer cells can get inside this vital compartment. Now they have discovered a previously unknown shortcut that some breast cancer cells use to metastasize to the leptomeninges, as well as clues that suggest how to block this path. Their study was published in June 2024 in the journal Science, with an accompanying commentary.
Sliding Down the Fireman's Pole
Physician-scientist Dorothy Sipkins (left) and postdoctoral associate Danhui Ma in the lab.
Sipkins, an associate professor of medicine, and her team showed in mice that breast cancer cells first infiltrated the bone marrow of the skull, then traveled via “emissary blood vessels.” These vessels begin in the bone marrow, pass through normal openings or “windows” in the skull, then become part of the leptomeninges.
“These tumor cells grab onto the outside of these blood vessels and basically shimmy down the vessel like a fireman sliding down a fireman’s pole,” Sipkins said. The work suggests a potential way to prevent cancer cells from taking this shortcut. “The cells in our study expressed a receptor called integrin alpha6 that they use to grab onto a specific protein that encases these blood vessels. Our evidence suggests that this protein, laminin, greases the fireman’s pole,” she said.
Preventing the Spread?
Sipkins hopes these findings will lead to a way to identify which women with breast-to-bone metastases are at highest risk for leptomeningeal disease. “If we can identify those patients by the presence of this marker integrin alpha6, could we prevent the spread?” she said. “And then for patients who already have the spread of the disease, what can we do for them?”
“We haven’t moved the dial in many years in terms of improving treatments for breast cancer patients with leptomeningeal metastasis,” Sipkins said. The disease is rare but is becoming more common as people live longer with breast cancer. “The symptoms that patients experience from this are debilitating. It’s a terrible complication,” she said.
After the team found out how breast cancer cells get inside the leptomeninges, they pushed further to figure out how the tumor cells survive there. Using their tool of choice — confocal microscopy — the researchers peered into the meninges and saw that the cancers cells stuck close to a particular type of immune system cell called macrophages. Then the tumor cells stimulated the macrophages to secrete a protein (glial-derived neurotrophic factor) that is normally used to protect neurons (brain cells). “We demonstrated that in our mouse models, glial- derived neurotrophic factor from meningeal macrophages was important for breast cancer cells to survive and proliferate, and to be successful in the meningeal microenvironment,” Sipkins said. She hopes to use this knowledge to develop new treatments.
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If we can identify those patients by the presence of this marker integrin alpha6, could we prevent the spread? And then for patients who already have the spread of the disease, what can we do for them?
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Dorothy Sipkins, PhD
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Associate Professor of Medicine
Key Donor Support
Sipkins praised her team’s dogged determination to find these answers. For example, post-doctoral associate Danhui Ma, PhD, spent countless hours learning new microscopy techniques and conducting final experiments, Sipkins said.
The initial work that went into this study would not have been possible without a philanthropic gift from David Wells, Sipkins said. Wells’ wife Leslie passed away after a brief battle with leptomeningeal disease, which she fought with the help of the Duke Center for Brain and Spine Metastasis. He made the gift in her honor. As a clinician, Sipkins treats patients with leukemia, and that is her main research focus. But she began studying breast cancer as well several years ago because it often spreads to the bone and bone marrow. This new study was inspired by some of her previous work in leukemia, in which she discovered that acute lymphoblastic leukemia cells can use this “fireman’s pole” method to spread to the leptomeninges.
Triple-negative breast cancer (TNBC) has long been considered one of the most aggressive and least understood forms of breast cancer. Defined by the absence of three key markers—estrogen receptor, progesterone receptor, and HER2 overexpression—TNBC represents a heterogeneous group of tumors that, until now, have largely been treated the same way.Researchers at the Duke Cancer Institute, led by Maggie DiNome, MD, surgical oncologist with the DCI breast oncology program, are working to change that.While TNBC tumors are classified as HER2-negative, many exhibit low levels of HER2 expression. Recent Duke studies reveal that this distinction is clinically significant.The analysis of a large national database showed that TNBC tumors with HER2-low expression respond less effectively to chemotherapy compared to those with no HER2 expression at all. This finding prompted deeper investigation into the molecular differences between these subtypes.The team discovered that HER2-low TNBC tumors exhibit an immune-evasive profile. These tumors and their surrounding microenvironment show reduced immune cell presence and hypermethylation of genes critical for immune recognition. This matters because the current standard of care for early-stage TNBC includes chemotherapy combined with immunotherapy yet over a third of patients do not respond to this combination therapy.“HER2-low tumors create an environment in and around the tumor that evades the immune system better than HER2-zero tumors,” DiNome said.Preliminary multicenter data suggest that patients with HER2-low tumors have a lower pathologic complete response rate to chemo-immunotherapy compared to those with HER2-zero. These findings could transform how clinicians approach TNBC treatment.“Not all patients respond to immunotherapy, and immunotherapies are not without pretty significant risk,” DiNome said. “If we can define the patient set that might not respond, we can save them from the morbidity of that treatment.”This research also opens the door to new strategies, such as combining immunotherapy with antibody-drug conjugates like trastuzumab deruxtecan, which has shown promise in HER2-low tumors.The DCI team is pursuing grant funding to explore mechanisms driving immune evasion and to test synergistic therapies that could improve outcomes for HER2-low patients. They are also investigating the role of epigenetic regulation and external factors, such as comorbidities, stress, and lifestyle, in shaping the immune environment.
Triple-negative breast cancer (TNBC) has long been considered one of the most aggressive and least understood forms of breast cancer. Defined by the absence of three key markers—estrogen receptor, progesterone receptor, and HER2 overexpression—TNBC represents a heterogeneous group of tumors that, until now, have largely been treated the same way.Researchers at the Duke Cancer Institute, led by Maggie DiNome, MD, surgical oncologist with the DCI breast oncology program, are working to change that.While TNBC tumors are classified as HER2-negative, many exhibit low levels of HER2 expression. Recent Duke studies reveal that this distinction is clinically significant.The analysis of a large national database showed that TNBC tumors with HER2-low expression respond less effectively to chemotherapy compared to those with no HER2 expression at all. This finding prompted deeper investigation into the molecular differences between these subtypes.The team discovered that HER2-low TNBC tumors exhibit an immune-evasive profile. These tumors and their surrounding microenvironment show reduced immune cell presence and hypermethylation of genes critical for immune recognition. This matters because the current standard of care for early-stage TNBC includes chemotherapy combined with immunotherapy yet over a third of patients do not respond to this combination therapy.“HER2-low tumors create an environment in and around the tumor that evades the immune system better than HER2-zero tumors,” DiNome said.Preliminary multicenter data suggest that patients with HER2-low tumors have a lower pathologic complete response rate to chemo-immunotherapy compared to those with HER2-zero. These findings could transform how clinicians approach TNBC treatment.“Not all patients respond to immunotherapy, and immunotherapies are not without pretty significant risk,” DiNome said. “If we can define the patient set that might not respond, we can save them from the morbidity of that treatment.”This research also opens the door to new strategies, such as combining immunotherapy with antibody-drug conjugates like trastuzumab deruxtecan, which has shown promise in HER2-low tumors.The DCI team is pursuing grant funding to explore mechanisms driving immune evasion and to test synergistic therapies that could improve outcomes for HER2-low patients. They are also investigating the role of epigenetic regulation and external factors, such as comorbidities, stress, and lifestyle, in shaping the immune environment.
