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Against four cells - why is there currently no effective drug for the treatment of glioblastoma brain cancer?

Glioblastoma, the most common and violent brain cancer, can wear many faces, and it changes its face not only from one patient to another - but also from one cell to another in the same patient. In a study recently published in the scientific journal Cell, scientists from the Weizmann Institute of Science, in collaboration with researchers from Boston, mapped the different faces of this cancer, and discovered that glioblastoma cells are found in one of four different "states", and can even switch between the different states. These findings may indicate directions for the development of future treatments for this incurable disease

Tissue nodules of glioblastoma tumors with cells in two different states, marked in red and blue
Tissue samples of glioblastoma tumors with cells in two different states, marked in red and blue

Glioblastoma, the most common and violent brain cancer, can wear many faces, and it changes its face not only from one patient to another - but also from one cell to another in the same patient. In a study recently published in the scientific journal Cell, scientists from the Weizmann Institute of Science, in collaboration with researchers from Boston, mapped the different faces of this cancer, and discovered that glioblastoma cells are found in one of four different "states", and can even switch between the different states. These findings may indicate directions for the development of future treatments for this incurable disease.

"Currently, there is no effective drug for the treatment of glioblastoma, and the reason for this may be that the existing drugs each only affect some of the states of the tumor cells," says Dr. Itai Tirosh from the Department of Molecular Biology of the Cell, who headed the research group together with Prof. Mario Soba from Massachusetts General Hospital (MGH) and the Broad Institute, both in Boston. "To eradicate cancer, future treatments will have to attack all four cellular conditions we have identified." The study was led by Julie Laffey of the Weizmann Institute of Science, Cyril Naftel and Mariela Philbin of MGH, and Toshiro Hara of the Salk Institute for Biological Research in California.

Dr. Itai Tirosh and Julie Lafi. The most common and violent brain cancer
Dr. Itai Tirosh and Julie Lafi. The most common and violent brain cancer

Dr. Itai Tirosh and Julie Lafi. The most common and violent brain cancer

It has been known for some time that cancerous tumors in general, and glioblastoma in particular, are not uniform, and actually contain different types of cells, but until now the existing technologies have provided only general information about gene expression in the entire cancerous tissue. In the new study, the scientists used an advanced technology of sequencing the genetic material at the single cell level. They examined samples from the tumors of 28 glioblastoma patients - 20 adults and eight children - and created a profile of gene expression in approximately 24 cancer cells. Using special algorithms they developed, the scientists revealed a correlation between patterns of gene expression and between cell division and other processes in the cell, and identified four cellular "states", each of which is characterized by its own gene activation program; Three of the identified programs are normally used by cells in the developing brain of the fetus, and two of them are used by stem cells. "The cancer cells actually 'ride' on the gene activation programs of cells in growth and development stages, harnessing them to the spread of the tumor," says Dr. Tirosh.

In some cells, different gene activation programs were operating simultaneously, and the scientists hypothesized that these cells were in the process of transitioning from one state to another. To find out, they attached a "barcode" to glioblastoma cells of mice, followed these cells over time and saw that the tumor cells did change from one state to another. In another experiment, the scientists transplanted glioblastoma cells taken from humans into mice, and saw that these cells, although they activated a certain genetic program, eventually developed into tumors that included the entire range of activation programs of the original tumor.

The four states of glioblastoma cells are represented by points in different locations - each corner represents a different state. The colors indicate the degree of cell division: black indicates cells that divide at the lowest rate, and red - cells that divide at the highest rate

In all the tumors examined in the study, more than one cellular condition was detected - and in most all four conditions were detected - but one condition was usually more common than the others. By analyzing data taken from the "Cancer Genome Atlas", the scientists revealed a correlation between the dominant cellular state in the tumor and the type of mutations that characterized it.

The precise characterization of glioblastoma cells, obtained thanks to the research, may help to develop new treatments that can intercept all four states of the tumor cells. Also, the findings may help in the characterization of other types of cancer.

About 3 out of every 100,000 people in the United States are diagnosed with glioblastoma brain cancer every year. This cancer is 1.6 times more common in men compared to women.

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