In two recently published studies, Weizmann Institute of Science scientists mapped common brain cancer tumors with unprecedented resolution, and identified a possible reason why some patients do not respond to a new treatment
The cells that make up cancerous brain tumors are extremely diverse and sometimes create unique three-dimensional structures. Already in 1932, the American neurosurgeon Percival Bailey tried to give them signs and discovered that several families of cells exhibiting similar properties can be identified in these tumors. Nine decades later, too little is still known about the identity of the cell groups that make up different types of brain tumors, about the orderly structures they create and how they affect the course of the disease and its treatment options. Accordingly, the success rates of the treatments for most of these types of cancer are usually not high.
In the past decade, the sequencing technology of genetic material at the single cell level has matured and today allows researchers to analyze in detail, at once, thousands of cells living in the same environment in the body, understand which genes they express, classify them into groups and learn about the role of each group. In the laboratory of Dr With me Tirosh in the department of molecular biology of the cell at the institute, in cooperation with the group of Prof. Mario Soba from Massachusetts General Hospital (MGH), harnessed this technology to re-dive into the open questions in the field of brain cancer.
The most common type of brain tumor is glioma - tumors that originate from supporting cells that help the nerve cells. Glioma tumors are divided into two - tumors with a mutation in the gene that codes for an enzyme called IDH, whose level of severity is usually low, and particularly violent tumors that do not have the same particular mutation in their cells and are called glioblastoma in the medical language. In studies from recent years, Dr. Tirosh's group deciphered the cellular composition of both types of tumors using methods of sequencing the genetic material at the single cell level. They discovered that the tumor cells are divided into groups, each of which expresses a unique gene program, which determines which biological "state" the cancer cells in the group will be in. Among other things, the researchers identified groups of cells that mimic normal cells in the brain through their unique gene programs.
Now, In a study recently published in the scientific journal Cell, scientists from Dr. Tirosh's laboratory, led by Dr. Elisa Greenwald, Noam Galili and Dr. Ruben Hoflin, harnessed technologies that allow not only to sequence the genetic material at the single cell level but also to map its expression in space. These methods allowed the researchers to identify for the first time which genes are uniquely expressed at each of the thousands of different points in the spatial structures of the brain tumors. In this way, the scientists were able to accurately map how glioblastoma and glioma tumors are organized in space. For this purpose, they examined samples from the tumors of 13 glioblastoma patients and 6 glioma patients with an IDH mutation.
The researchers' first discovery was that the different groups of cells within glioma tumors are not evenly distributed throughout the tumor, but are concentrated in different environments within the tumor. Those microenvironments are not completely homogeneous, since in the vicinity of cells of a certain type, members of other groups could always be found. In the next step, the researchers checked if there are groups of cells in the tumor that usually live in the neighborhood of each other and discovered that not only are there preferred neighbors, but that these pairings of good neighbors are consistent in different patients.
Certain pairs of neighbors mimicked the natural behavior of brain tissue: for example, cells that mimic oligodendrocyte-type progenitor cells were found near endothelial cells, cells that make up the blood vessel wall. This pairing also takes place in the healthy tissue, as endothelial cells secrete substances required for the survival and proliferation of pre-oligodendrocyte cells. Similarly, cells that mimic neural progenitor cells reside in the tumor in areas where it penetrates into healthy brain tissue, just as progenitor cells in healthy tissue migrate as it regenerates. And yet, most of the discovered pairings are not fully understood.
At a glance, the researchers identified that the organization of the groups of cells in separate environments in the tumor created five distinct layers. The inner layer or core of the tumor, is necrotic tissue where cells do not receive enough oxygen to survive. In the layer around the necrosis, fetal connective tissue-like cells and other cells were found, including cells of the immune system responsible for inflammatory conditions. In the third layer it was possible to find mainly blood vessels, endothelial cells that make up the wall of blood vessels, as well as other cells of the immune system.
In the two outermost layers of the tumor, the cells no longer suffer from a lack of oxygen. This fact enables the development of groups of tumor cells that mimic normal brain tissue in the fourth layer - progenitor cells of nerve cells and support cells. The outermost layer includes the healthy brain tissue into which the tumor penetrates. The findings on the different layers of the tumor indicate that the force that drives the tumor to arrange itself in a layered structure is the lack of oxygen that intensifies with the progression of the disease and the development of the tumor.
According to their findings, the scientists noticed that tumors of a lighter grade - which are usually also smaller - as well as areas of the tumor with a good oxygen supply presented a chaotic structure. For example, in glioma tumors with mutant IDH, there was usually no necrotic tissue and they presented an irregular structure; In the exceptional cases where there was necrotic tissue, the samples also had a fairly orderly structure.
"We discovered that the orderly spatial structure characterizes aggressive tumors with a higher degree of severity," explains Dr. Tirosh. "The oxygen level in the living environment of the tumor cells affects the gene program they express and thus their condition. In this organization of the tumor, distinct layers are formed that can be less accessible to drugs and the cells of the immune system, and thus they may make the tumor more resistant."
Cancer cells change status
In Dr. Tirosh's laboratory, they used the knowledge they had gained about the composition of the cells in glioma tumors in order to understand How a promising new drug is helping some patients with this cancer. To this end, the scientists used samples from cancer tumors of three patients who participated in the clinical trial of the drug and responded to treatment, as well as six samples from patients who were not treated at all. To complete the picture, they also relied on sample data from 23 patients who were treated with the drug and 134 patients who were not treated with it.
The scientists, led by Dr. Avishai Spitzer, recognized that the drug, which works through a mechanism that inhibits the production of the IDH enzyme in its cancerous version, causes the cells to change the gene program they express. In fact, the treatment encourages the cancer stem cells to differentiate into mature cells, thus impairing their ability to divide quickly - and the progression of the disease is slowed down.
The scientists hypothesized that if the drug works through the differentiation of cancer stem cells into mature cells, a mutation affecting the gene essential for the differentiation process may explain the cases in which the drug does not work. In samples from patients who were not treated with the drug, they identified a mutation in a certain gene that is associated with a low rate of mature cancer cells and a high rate of cancer stem cells. When they silenced the same gene in a cancer model in mice, they saw that the drug did not lead to the expected therapeutic effect. "This finding shows that a mutation in the gene we identified can be a biological marker that will make it possible to distinguish in advance between patients who will benefit from the treatment and those who will not," explains Dr. Tirosh. The new findings may also help in finding a treatment that combines IDH inhibitors with another drug that will encourage the differentiation process and increase the effect of the treatment on the cancer tumor.
"Our two latest studies reveal the forces that shape the nature of the cancer cells in brain tumors, whether it is their living environment within the tumor or a pharmacological intervention that changes the gene expression program in the cells," concludes Dr. Tirosh. "These findings open a window to a new approach to cancer treatment, since if we know the groups of cells that inhabit each area of the cancer tumor and know how a cell can switch from one state to another, we may be able to develop new targeted treatments that will change the course of the disease. The understanding that the composition of the cells within the tumor and its three-dimensional structure are related to the degree of aggressiveness can also give rise to new diagnostic methods that do not rely only on the volume of the tumor and its mutations."
Dr. Dor Simkin, Yotam Harnik and Dr. Julie Lafi from the department of molecular cell biology at the institute also participated in the research on the structure of glioma tumors; Dr. Christopher Mount, Dr. Nicolás González Castro, Sidney Dumont, Dr. Masashi Namura, and Dr. Vamsi Mangina from Massachusetts General Hospital (MGH) and Harvard Medical School in Boston, USA; Dana Hirsch from the Department of Veterinary Resources at the Institute; Tom Telfair from the department of computer science and applied mathematics at the institute; Dr. Mirav Kadami, Dr. Ina Goliand, Dr. Hadas Keren-Shaul and Dr. Yosef Addi from the Department of Life Sciences Research Infrastructures at the Institute; Joel Medici, Prof. Michael Weller and Dr. Marian K. Neidert from the University Hospital of Zurich, Switzerland; and Dr. Baugo Lee from the Department of Systemic Immunology at the Institute.
Dr. Roni Hanoch-Meyers from the department of molecular cell biology at the institute also participated in the research on the treatment with mutant IDH inhibitors; Dr. Simon Gretsch, Dr. Masashi Namora, Hanna Weissman, Dr. Nicholas Gonzalez Castro, Nicholas Drake, John Lee, Ravindra Milwagnam, Rachel Lee Service, Jeremy Mann Fang, Prof. Christine K. Lee, Dr. Hiroaki Nagashima, Prof. Julie Miller, Dr. Isabel Arillaga-Romney, Dr. David Lewis and Prof. Hiroaki Wakimoto from Massachusetts General Hospital (MGH) and Harvard Medical School in Boston, USA "on; Dr. Jerome Fortin of the Princess Margaret Cancer Center in Toronto and McGill University in Montreal, Canada; Dr. Ramya Raviram, Prof. Dan Landau and Dr. Daniel Cahill from the Genome Center of New York, USA; Will Pisano and Prof. Keith Ligon from Brigham and Women's Hospital in Boston, USA; Prof. Patrick Won from the Dana-Farber Cancer Institute of Harvard University in Boston, USA; Prof. Teck Mak from the University of Hong Kong; Prof. Marc Sanson and Dr. Mehdi Tuat from Sorbonne University in Paris, France.
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