Glioblastoma (GBM) remains one of the most lethal forms of brain cancer, with a median survival rate of just over a year. Despite aggressive treatments including surgery, radiation, and chemotherapy, nearly all tumors eventually recur. Researchers at the Sylvester Comprehensive Cancer Center, in collaboration with international partners, have uncovered a new explanation for this resilience: GBM cells that disperse from cell clusters develop a dangerous adaptability known as plasticity, enabling them to resist treatment.
“This gives us a much better grasp of the biology of glioblastoma, a tumor type where a lot still remains to be discovered,” stated Dr. Anna Lasorella, senior author of the study recently published in Cancer Cell.
Mapping Tumors Cell by Cell
The research team, co-led by Dr. Antonio Iavarone, employed spatial transcriptomics—a cutting-edge gene-expression mapping technology known as the CosMx platform—to analyze thousands of individual cells within patient tumors. This innovative approach not only identifies which genes are active but also locates each cell in relation to its neighbors.
In previous studies, the group had identified four molecular subtypes of GBM cells. This time, they investigated how these subtypes are arranged within tumors. They discovered that while cells of the same subtype often form clusters, some cells disperse into mixed areas. It is these dispersed cells that are particularly concerning.
Dispersed Cells: More Plastic and Aggressive
By comparing gene expression profiles, the researchers found that dispersed cells lack key adhesion molecules that typically help cells stick together. Concurrently, they express genes associated with plasticity, which allows them to change identity and behavior.
“There has never really been an integrated explanation as to why cancer cells develop plasticity,” Iavarone explained. “That’s what our study does. We’ve now revealed how the plasticity of glioblastoma cells is controlled.”
Plasticity is clinically significant because it is linked to therapy resistance and poor patient outcomes. The team speculates that standard treatments, such as radiation or chemotherapy, might inadvertently cause clusters to break apart, leading to more dispersed, treatment-resistant cells.
A Principle That May Extend Beyond Brain Tumors
The researchers also examined breast cancer samples, where they observed a similar pattern: dispersed cells were more plastic than clustered ones. This suggests that the loss of cell–cell adhesion may be a general driver of solid tumor aggressiveness, even though GBM itself rarely metastasizes.
“We think this principle is of general significance for solid tumors,” said Iavarone. “It provides an answer to why certain cells become so aggressive.”
Toward Therapies That Keep Cells “Stuck”
The findings suggest an unexpected therapeutic angle: encouraging tumor cells to remain clustered might limit plasticity and slow disease progression.
“If we can better understand this mechanism, we hope to one day be able to maintain the clustered cells that are less plastic in that state, or even reverse the dispersal of these more plastic cells,” Lasorella said.
Future research will focus on identifying the adhesion proteins that help cells stay together and on testing whether strengthening those molecular bonds can counteract GBM’s deadly adaptability.
Implications for Future Cancer Treatments
Glioblastoma’s ability to recur and resist treatment remains a significant clinical challenge. By demonstrating that cellular architecture influences tumor behavior, this study suggests new biomarkers—such as the proportion of dispersed versus clustered cells—that could refine prognosis or guide therapy. If the same biology holds in other cancers, drugs designed to preserve or restore cell clustering might one day complement existing treatments across multiple solid tumors.
As researchers continue to unravel the complexities of cancer cell behavior, these insights could pave the way for more effective treatments and improved outcomes for patients facing some of the most aggressive forms of cancer.
