New study uncovers why dispersed glioblastoma cells are more dangerous

A new study, led by researchers at Sylvester Comprehensive Cancer Center part of the University of Miami Miller School of Medicine, captured details of glioblastoma that had never before been seen and revealed a surprise finding: Glioblastoma cells that "cluster" together with other cells of the same type are less deadly than those that disperse from these clusters. The findings were also corroborated in breast cancer samples and point to a possible new general principle of solid tumor biology.

The study was led by Anna Lasorella, M.D., co-director of the Sylvester Brain Tumor Institute (SBTI) and director of Sylvester's Precision Medicine Initiative, and Antonio Iavarone, M.D., director of the SBTI and deputy director of Sylvester. The team published a paper describing their findings Sept.18 in the journal Cancer Cell.

"This gives us a much better grasp of the biology of glioblastoma, a tumor type where a lot still remains to be discovered," said Lasorella, who is senior author on the paper.

Better understanding glioblastoma is critical-the cancer is highly deadly, with an average survival time of only slightly more than a year after diagnosis. Glioblastoma nearly always recurs following initial treatment, and the recurring tumors are always resistant to therapy.

The study offers a new possible explanation for why the cancer is so difficult to treat. The researchers found that "dispersed" cells in the tumor are more plastic, a biological term for cells that are malleable and able to shift to different forms or states. Plasticity is an unwelcome attribute for cancer; it correlates with treatment resistance and poorer outcomes for the patient. But what drives cancer plasticity has, to date, remained a mystery.

"There has never really been an integrated explanation as to why cancer cells develop plasticity," said Iavarone. "That's what our study does. We've now revealed how the plasticity of glioblastoma cells is controlled."

Initial treatment of the brain tumors with chemotherapy or radiation could actually break up the less harmful clusters of cancer cells and spur them to disperse, the researchers said, meaning those cells left behind after treatment become more plastic and thus more harmful to the patient. That hypothesis remains to be tested, but it is clear that the dispersed cells and the clustered cells behave very differently in the tumor.

The team's findings were made using the CosMx platform, which allows researchers to pinpoint individual cells in a tumor or other tissue sample by profiling thousands of genes that are switched on or off in those single cells. The technology, known as spatial transcriptomics, yields information about different kinds of cells present in a single tumor and their precise locations compared to their neighboring cells.

In previous studies, Lasorella, Iavarone and their colleagues had identified four different types of glioblastoma cells based on the specific genes switched on in each kind of cell. In the current study, they looked at how these four types of cells are arranged in tumors. They found that all four types form clusters of the same kind of tumor cell, as well as areas of the tumor where the types are mixed together, which the scientists call the dispersed type.

Delving further into the differences between clustered and dispersed cancer cells, the researchers found gene expression differences between the two that indicated that the dispersed cells are more plastic than those in clusters. They also found that clustered cells express proteins on their surfaces that help them stick together; the dispersed cells are missing those proteins. 

The researchers found that the same principles apply in samples isolated from patients with breast cancer - dispersed breast cancer cells were more plastic than those found in clusters. Cancer cell plasticity drives solid tumor metastasis, or cancer spread. Although glioblastoma doesn't metastasize in the same way that other solid tumors do, understanding why and how cancer cells become plastic is likely to shed light on why and when many cancers metastasize, the researchers said.

"We think this principle is of general significance for solid tumors," said Iavarone. "It provides an answer to why certain cells become so aggressive."

The researchers hope their discoveries could point to a new possible treatment avenue for glioblastoma. They're following up their findings about how the tumor cells stick together in clusters to discover whether it is possible to promote that clumping, thus preventing cells from dispersing and becoming more plastic.

They've shown that disrupting the adhesion leads to more dispersed cells in pre-clinical models of glioblastoma, but proving the opposite will be more difficult. The researchers are also asking whether the dispersed cells express certain proteins or molecules that disrupt adhesion and, if so, whether those proteins could be possible drug targets.

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."

Anna Lasorella, M.D., co-director of the Sylvester Brain Tumor Institute (SBTI) and director of Sylvester's Precision Medicine Initiative