Freezing brain tumor cells in sleep mode
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Every brain tumor is made up of cells in successive stages of activation. Researchers from the German cancer Research Center (DKFZ) and Heidelberg University have now analyzed the individual structure of these activation pyramids in malignant brain tumors for the first time. They discovered a signaling protein that slows down the transition from a dormant to an activated state by epigenetically reprogramming the cancer cells. The hope is to permanently freeze cancer cells in a dormant state and thus halt tumor growth.
Glioblastoma is the most common and most aggressive form of brain tumor in adults. Despite surgery, radiotherapy and chemotherapy, the tumors usually return within a few months after treatment. As with many other types of cancer, growth in glioblastoma is driven by cancer stem cells, from which tumor cells emerge in various stages of activation that merge into one another.
"You can imagine the composition of glioblastoma cells as a pyramid: The quiescent cells form the base, followed by those activated to divide, and at the top are the so-called differentiated tumor cells, which actually have some characteristics of nerve cells," explains study leader Ana Martin-Villalba from the DKFZ.
Many cancer therapies are not sustainable because they target the dividing tumor cells, for example, but their losses are quickly replenished from the population of quiescent cells at the base of the pyramid. "It is therefore important to understand which molecular signaling pathway is responsible for the transition between these two states of activity. Then we can specifically look for a drug to block it," says the scientist. However, these molecular pathways and the dynamics with which the different activation states transition into one another have so far been an aspect of tumor biology that has received little attention.
This is now changing with the current work of Martin-Villalba's team. The Heidelberg researchers developed an innovative analysis method based on single-cell mRNA sequencing, which enabled them to systematically map the activation states of glioblastoma cells for the first time. To do this, they compared the molecular profiles of tumor cells from 55 glioblastoma patients with those of healthy neural stem cells from the mouse brain. "For the first time, we were able to determine the individual structure of the pyramid for each patient - a previously underestimated aspect of tumor biology," explains Leo Carl Foerster, one of the two lead authors of the study.
Proportion of dormant cells best marker for slow tumor growth
A key finding: the higher the proportion of dormant tumor cells at the base of the pyramid, the slower the glioblastoma grows - and the better the prognosis for those affected. By comparing the gene expression dynamics in healthy cells and tumor cells, the team discovered that the expression of the signaling protein SFRP1 is misregulated during the transition from the dormant to the activated state. SFRP1 inhibits the important Wnt signaling pathway, which is important for the activation of stem cells, among other things.
In mouse models, overexpression of SFRP1 was able to significantly slow tumor growth. "Using SFRP1, we were able to put human tumor cells into sleep mode. This not only slows down their growth, but also significantly prolongs the survival of the mice," reports Oguzhan Kaya, also first author.
Cancer cells frozen in a dormant state?
Under the influence of SFRP1, the tumor cells not only changed their activity, but also their epigenetic profile - i.e. the "memory" of their cell identity. They developed characteristics of mature astrocytes, i.e. brain cells that no longer have the ability to divide. This epigenetic reprogramming could potentially help to prevent the return of tumors in the future: The epigenetic methyl marks on the genome restrict cellular mutability by limiting the genome to the specific functions of differentiated cells.
The researchers also found that determining the epigenetic methyl profile maps the composition of each tumor's individual activation pyramid and can therefore be used to stratify patients.
In future work, the Heidelberg team plans to investigate whether SFRP1-mediated remodeling of methylation can permanently "freeze" glioblastoma cells in a dormant state. This could open up a potential therapeutic approach against diseases such as glioblastoma that have so far been almost impossible to control. "Our results confirm that killing active cancer cells is not the only decisive factor, but that blocking the transitions between activity and dormancy is crucial for the outcome of a therapy," says Ana Martin-Villalba, summarizing the results of the work.
Note: This article has been translated using a computer system without human intervention. LUMITOS offers these automatic translations to present a wider range of current news. Since this article has been translated with automatic translation, it is possible that it contains errors in vocabulary, syntax or grammar. The original article in German can be found here.
Original publication
Leo Carl Foerster, Oguzhan Kaya, Valentin Wüst, Diana-Patricia Danciu, Vuslat Akcay, Milica Bekavac, Kevin Chris Ziegler, Nina Stinchcombe, Anna Tang, Susanne Kleber, Joceyln Tang, Jan Brunken, Irene Lois-Bermejo, et al.; "Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression"; Nature Communications, Volume 16, 2025-8-6
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