Changing Identity to Survive: How Brain Tumors Evade Treatment
Imagine a war against an enemy that not only multiplies, but actually changes its identity in order to survive. That is the reality of treating gliomas, the most common primary brain cancer in adults. Patients diagnosed with an IDH-mutant glioma usually face a long and complex course. These tumors most often appear in people in their 20s to 40s, and although they grow more slowly than other aggressive brain cancers, they almost always return despite surgery, chemotherapy and radiation. 3 View gallery Brain cancer of the glioma type (Photo: shutterstock)
For years, scientists have tried to understand how these tumors adapt under treatment pressure and become resistant. Now, in an international study published in the journal Nature, this evolutionary journey was mapped at unprecedented single-cell resolution. The study was conducted in collaboration with leading scientists from Harvard, Yale and the University of Miami, as well as research partners from other countries, and was based on genomic profiles of 75 tumor samples collected over time from 35 patients, comparing the original tumor with the tumor that recurred years later.
What is an IDH-mutant glioma? At the root of these tumors lies a specific genetic error in the IDH1 or IDH2 genes. This mutation completely changes the cell’s internal mechanism and causes massive production of a rogue molecule called 2HG. This molecule acts like an epigenetic wedge, blocking the normal chemical changes in DNA and effectively locking young, immature brain cells in a state of developmental arrest. Since they cannot mature into healthy, functioning brain tissue, the cells continue dividing without pause and eventually form a tumor. Historically, scientists saw tumors as uniform masses of cells, but single-cell sequencing shattered that illusion. In IDH-mutant gliomas, several main cell states can be found, rapidly dividing cells resembling neural stem cells, and partially "differentiated" cells that resemble normal brain cells, astrocytes or oligodendrocytes. 3 View gallery Right, Prof. Itay Tirosh and Dr. Avishai Spitzers (Photo: Lior Zur, Ichilov spokesperson; Weizmann Institute of Science)
The scientific community lacked a detailed model of how treatment shapes the evolution of these tumors over time. Do treatments selectively kill certain cell types and leave behind only the most aggressive ones? Or do the treatments themselves force tumor cells to adapt and adopt completely new identities? To answer this, genomic profiles from dozens of patients collected over time were examined. Using single-cell RNA sequencing and tracking DNA accessibility to transcription factors, the scientists were able to look inside individual tumor cells and see which genes were active, how the DNA was packaged, and how their internal architecture changed over years of treatment.
Two evolutionary pathways
The long-term analysis led to a major discovery, IDH-mutant gliomas use two separate and parallel evolutionary pathways to progress and develop treatment resistance. "Clinically, this translates into slower tumor growth, a lower chance of accumulating harmful genetic events, delayed disease progression, and ultimately a significant extension of patients' lives."
The first pathway is directly tied to the genetic scars left by chemotherapy and radiation. Patients who received standard chemoradiation often accumulated a huge burden of new DNA errors, a phenomenon known as hypermutation. When the tumor acquired these major genetic changes, the cellular proportions within it changed completely. Differentiated, nondividing cells nearly disappeared, and in their place primitive, highly proliferative and highly flexible cells flourished, pushing the tumor back up the developmental ladder toward a more aggressive and less differentiated state.
The second pathway surprised the researchers: the tumors also advanced by shifting into a highly reactive, aggressive connective tissue-like state, a mesenchymal state, without any new genetic changes. This shift was driven by the tumor microenvironment. Radiation changes the local immune landscape and promotes massive recruitment into the tumor of bone marrow-derived immune cells, macrophages, which signal the tumor cells to move into this defensive and resistant state. Patients whose recurrent tumor had a high proportion of mesenchymal cells experienced significantly shorter survival.
The crucial role of cell differentiation
To understand why these changes are critical, one should look at a previous study published in the journal Cancer Cell, which showed that a new group of targeted drugs, mutant IDH inhibitors, can reverse the effect of the original mutation. In patients who respond to treatment, these inhibitors remove the epigenetic block and allow the aggressive, stem cell-like tumor cells to mature, differentiate and resemble mature brain cells.
The process of differentiation is a vital therapeutic goal because differentiation and the ability to divide are fundamentally opposing traits. When treatment removes the block and allows cells to return to their natural maturation path, their ability to divide is inherently reduced. Clinically, this translates into slower tumor growth, a lower chance of accumulating harmful genetic events, delayed disease progression, and ultimately a significant extension of patients' lives.
"These insights do not mean that traditional chemotherapy and radiation should be abandoned, they are critical tools that prolong patients' survival. However, the new data indicate that the timing of these treatments is crucial." These insights do not mean that traditional chemotherapy and radiation should be abandoned, they are critical tools that prolong patients' survival. However, the new data indicate that the timing of these treatments is crucial. The standard combination of chemotherapy and radiation acts as a double-edged sword, it destroys cancer cells but is toxic to differentiation. Over time, the accumulation of mutations and genetic scars from chemotherapy and radiation, together with the inflammation produced by macrophages, disrupts cell differentiation and pushes the tumor toward loss of differentiation and expansion of aggressive cell populations. Since it is impossible to predict exactly when the tumor will reach this tipping point, the treatment strategy must take this into account. 3 View gallery Chemotherapy is not abandoned, but IDH inhibitors are added as first-line treatment. Illustration (Photo: shutterstock)
Instead of exposing patients to differentiation-disrupting treatments at the outset, the goal should be to use IDH inhibitors as first-line treatment. This can first promote cell differentiation, reduce the population of dangerous stem-like cells and restrain tumor growth, while preserving the basic cellular structure. Only later, when the targeted inhibitors stop working, can there be a strategic and calculated transition to chemotherapy and radiation. Designing the clinical timeline around the different cell identities will maximize the differentiation window, delay the emergence of resistance and give patients a meaningful advantage for a much longer period.
Ultimately, understanding these evolutionary mechanisms will not only improve the combination of existing treatments, but also pave the way for the discovery of new drugs that encourage cell differentiation, and change the way we deal with one of the most challenging types of cancer.
Dr. Avishai Spitzers, a physician-scientist and medical oncology resident at Ichilov Medical Center, is an expert in computational cancer genomics and research in neuro-oncology. The studies described were conducted as part of Dr. Spitzer’s doctoral work at the Weizmann Institute of Science under the supervision of Prof. Itay Tirosh.
