Researchers at the German Cancer Research Center (DKFZ) and the University of Heidelberg have developed an innovative approach to combat glioblastoma, the most aggressive form of brain tumor in adulthood. Using single-cell mRNA sequencing, they mapped the activation stages of tumor cells for the first time and identified the signaling protein SFRP1, which epigenetically inhibits the transition from dormant to active cancer cells. This mechanism could slow tumor growth and prevent tumors from returning by “freezing” cancer cells in a dormant state.

Glioblastomas are characterized by their rapid return after surgery, radiation, and chemotherapy, driven by cancer stem cells that form a pyramid of activation stages: dormant cells at the base, division-active cells in the middle, and differentiated, nerve cell-like cells at the top. Conventional therapies often target cells that are active in division, but these are quickly replaced from the base of the dormant cells. The Heidelberg study shows that a high proportion of dormant cells is associated with slower tumor development and a better prognosis for patients.

By comparing gene expression profiles of tumor cells in 55 glioblastoma patients with healthy neuronal stem cells in mice, the researchers developed an analytical method that represents the individual composition of these activation pyramids. A key discovery was the dysregulation of the signaling protein SFRP1, which inhibits the Wnt signaling pathway, which is essential for stem cell activation. In mouse models, overexpression of SFRP1 led to a significant slowing of tumor growth as tumor cells were put into a dormant state. In addition, SFRP1 altered the epigenetic profile of the cells, causing them to take on characteristics of mature, non-dividing astrocytes.

Epigenetic reprogramming by SFRP1 could prevent the return of glioblastomas by restricting the cells’ ability to mutate by methyl markers on the genome. The determination of the epigenetic methyl profile also enables stratification of patients in order to adapt therapies more individually. The researchers plan to conduct further studies to test whether SFRP1-based approaches can keep tumor cells permanently inactive. These findings could form the basis for new therapies against glioblastomas, which have so far been difficult to control, and emphasize the importance of not only fighting active cancer cells, but also blocking the transitions between activation stages.

Original Paper:

Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression | Nature Communications

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