Research News

A new Cleveland Clinic model simulates how the organization of cells within our brains promotes breast cancer brain metastasis (BCBM). Researchers mapped interactions between tumor cells that spread to the brain and star-shaped, noncancerous brain cells called astrocytes. Published in Bulletin of Mathematical Biology, the digital model lets researchers explore how astrocytes are arranged within our brains.

Understanding how healthy cells in a tumor microenvironment help the cancer grow is important for future treatment strategies, first author Rupleen Kaur explains. Cancer cells mutate quickly, which makes them likelier to evolve treatment resistance. Noncancerous cells rarely mutate, so it may be easier to target those cells to block tumor growth.

“We know by now that the tumor microenvironment plays a key role in helping metastatic cancer cells form tumors far away, but we don’t know much about how the organization of that environment plays a role,” says Kaur, an MD-PhD candidate in the laboratory of study lead author Andrew Dhawan, MD, DPhil. “Our model lets us study the tumor microenvironment as a dynamic, evolving ecosystem.”

Why do we need to model different patterns in which brain cells can be organized?

Cancer cells trick, or “reprogram,” astrocytes into helping tumors grow and resist treatment. Studying this process is difficult because the brain environment is very different than a petri dish. Some parts of the brain are astrocyte-rich, and others have few. The gray and white matter in the brain also have very different patterns of astrocyte organization. These cell-level patterns are too small and intricate to map out using current methods, even with an MRI.

Kaur’s model allows users to manipulate factors including cell density and astrocyte distribution within the brain. These tests can show how tissue structure affects metastasis growth.

“We wanted to answer many questions with our model. Are BCBM tumors in astrocyte-rich regions of the brain more aggressive? Do we need to treat them differently?” Kaur says. “We can’t answer those questions until we can answer this one: how sensitive is metastatic growth to the physical structure of the microenvironment in the brain?” 

According to the Dhawan Lab’s model, the answer is very sensitive.

What did the model show?

Across thousands of simulations:

• BCBM tumors in astrocyte-dense environments were almost twice as large as tumors in astrocyte-poor environments.
• The presence of astrocytes also changed the tumors’ shape, creating irregular, "raggedy" edges linked to aggressive behavior.
• Tumors grew differently when astrocytes were clustered versus evenly spaced, even at the same average density.
• Astrocyte-rich regions form “chemoprotective pockets,” where computer simulations predicted the BCBM tumors would resist chemotherapy and treatment.

The Dhawan Lab’s findings complemented work by Cleveland Clinic’s Peiwen Chen, PhD, whose research has shown that immune cells in the brain can also promote metastasis and chemotherapy resistance.

“Cleveland Clinic is home to leading experts in breast cancer brain metastasis research, with each of us approaching the challenge from different angles,” Dr. Dhawan says. “Together, our data show the microenvironment matters as much as the tumor. By targeting the support structures that help cancer persist, we could reduce the lethality and even occurrence of brain metastases.”