Brain tumors in children: mapping vulnerabilities in dormant cancer cells

The “Hopp Children's Cancer Center Heidelberg” (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and Heidelberg University (Uni HD).

Low-grade gliomas account for almost half of all brain tumors in children but have been little studied to date. The tumors are usually benign and young patients generally have a good survival rate. Nevertheless, the children suffer from symptoms and have to contend with the effects of the disease and treatment for the rest of their lives.

Highly complex signaling pathways determine the behavior of our body’s cells. Those that are particularly prone to becoming cancerous often leave their normal cell cycle and enter a dormant state known as senescence. Senescent cells are in a kind of ‘hibernation’: they do not divide and therefore cannot initially multiply uncontrollably. This process is therefore considered an important protective function in preventing the development of cancer. Cancer treatments such as chemotherapy and radiation can also trigger the senescence process and force cancer cells into this dormant state.

In low-grade gliomas, however, the process of senescence is a double-edged sword: although the cells in their dormant state do not divide, they simultaneously release pro-inflammatory proteins and growth factors into their environment, which can lead to tumor growth and relapses. Since they are no longer actively dividing, the ‘sleeping’ cells also escape destruction by chemotherapy. Intensive research is therefore currently underway to find out how cellular senescence functions are controlled to find newtherapeutic agents called senolytics to destroy them.

A team of researchers from the Hopp Children's Cancer Centre Heidelberg (KiTZ), the German Cancer Research Centre (DKFZ) and the University Hospital Jena (UKJ) has now succeeded for the first time in comprehensively mapping the key genes and proteins that put cells into a dormant state. They analyzed the proteins and gene activity of ‘sleeping’ cells before and after treatment with the cancer drug trametinib in a cell culture from tissue samples of pilocytic astrocytoma, a very common form of low-grade glioma in children and adolescents.

Trametinib fights cancer cells by blocking the MAPK signaling pathway, which is overactive in many low-grade gliomas due to genetic changes. As the present study now shows for the first time, this signaling pathway also controls the resting state of cancer cells. The blockade of the MAPK pathway with Tremtinib switches off senescence but cancer cells also become resistant to senolytics. 

The blockade of the MAPK pathway also allowed the researchers to identify the set of genes and proteins under the control of the MAPK pathway and responsible for the activation of this dormant state. This set of molecules was investigated in tissue samples from patients, where gene activity was dependent on whether young patients had a favorable or unfavorable prognosis had a stronger expression of these. This expression pattern could therefore be used as prognostic markers for low-grade gliomas in the future. 

The results clearly show how important it is to tailor the treatment plan to each individual patient and to know the genetic makeup of the tumor, the researchers emphasize in their publication. Based on the results of the study, the research team plans to validate the findings in preclinical studies to lay the groundwork for prospective clinical trials aimed at delivering urgently needed therapeutic options for children with low-grade gliomas.

 

Original publication:
Sigaud, R., Stefanski, A., Selt, F. et al. Multi-omics dissection of MAPK-driven senescence unveils therapeutic vulnerabilities in KIAA1549::BRAF-fusion pediatric low-grade glioma models. In: Sig Transduct Target Ther 10, 197 (2025). https://doi.org/10.1038/s41392-025-02279-8