Brain tumors in children: Cancer cells become less aggressive as they migrate within the tumor
Certain brain tumors in small children contain cells that develop very similarly to normal brain cells and others that have already developed malignantly, depending on where they are located within the tumor. By analyzing individual cells, a team of researchers from the Hopp Children's Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD) were able to characterize the genetic programs of the individual cells in detail and identify their developmental pathway within the tumor.
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).
Microscopic image of the tumor cells, which develop differently depending on the tumor area. Right: Turquoise and beige cells are rapidly dividing, early tumor cells, green and red are more mature stages and purple are connective tissue and auxiliary cells of the tumor.
© Ghasemi/KiTZ
Medulloblastoma are among the most common solid tumors in children and the most common malignant brain tumor in children. The tumor grows in the cerebellum and can damage vital brain centers as it grows.
Based on tissue characteristics and genetic criteria, medulloblastomas are now divided into different risk groups, which can take a completely different course. While certain subtypes progress aggressively and form metastases, there are other forms that can usually be cured with an intensive combination therapy of surgery, chemotherapy and radiotherapy.
A team of researchers from the Hopp Children's Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD) has now used a novel method to investigate what directs certain tumors in a more benign or malignant direction at the cellular level.
A certain type of medulloblastoma, which is characterized by its good chances of recovery and at the same time by the special structural properties of its tissue, served as a model for them: in so-called medulloblastoma with extensive nodularity (MBEN), small tissue chambers are delimited within the tumor, which are connected in a grape-like manner. The study showed that tumor cells located in these nodules were no longer actively dividing and their genetic program was similar to that of mature brain cells. In the intermediate areas, however, the scientists identified different cell types: In addition to immune and connective tissue cells, there were also significantly more aggressive tumor cells that continued to divide uncontrollably and whose genetic program was more similar to those of fast-growing medulloblastomas and immature nerve cells. In the course of their migration into the nodes, however, the cancer cells matured back into nerve-like cells and no longer divided.
Kristian Pajtler, a pediatric oncologist at KiTZ, DKFZ and UKHD and head of the study, explains the results as follows: "In some childhood tumors, the normal development process is blocked. The cancer cells thus become similar to immature precursor cells, which remain active in division due to a specific genetic program. In MBEN tumors, this apparently only works partially and many of the cells then go through the halfway normal development process of a cerebellar cell and stop dividing. This would also explain the mostly favorable course of this type of tumor."
For their analyses, the team dissected the tumors of nine young MBEN patients into their individual cellular components and analyzed the genetic program of the individual cells. Using a bioinformatic method, they were then able to reconstruct where exactly these cells were located within the tumor. The method, which was used in collaboration with Karsten Rippe's department at DKFZ, is of particular importance for medulloblastoma research, explains one of the two lead authors of the study, David Ghasemi, physician and scientist at KiTZ, UKHD and DKFZ. "Until now, it has never been possible to develop laboratory models for this type of medulloblastoma. Only with this method was it possible to localize the individual cell types within the tumor and to understand how the various areas within the tumor differ from each other."
Blocking the maturation process is an important therapeutic tool that is already being researched in order to avert malignant progression in children and steer the cancer cells back in a benign direction. "It is possible that MBEN tumors only need a little push here," says Kristian Pajtler. "Because even if most children with an MBEN tumor can be cured by surgery and, if necessary, further therapies, these are very intensive treatments for small children, which are often associated with severe, lifelong side effects."
Original publication:
Ghasemi D.R., Okonechnikov K. et al. Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage. In: Nature Communications (Online Publication 8th of January, DOI: 10.1038/s41467-023-44117-x)
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Caption:
MRI image: In so-called medulloblastoma with extensive nodularity (MBEN), small tissue chambers are delimited within the tumor and are connected in a grape-like manner.
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The Hopp Children's Cancer Center Heidelberg (KiTZ)
The „Hopp Children's Cancer Center Heidelberg" (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital and Heidelberg University. As the National Center for Tumor Diseases (NCT), which focusses on adult oncology, the KiTZ is based on the US model of so-called "Comprehensive Cancer Centers" (CCC). As a therapy and research center for oncologic and hematologic diseases in children and adolescents, the KiTZ is committed to scientifically exploring the biology of childhood cancer and to closely linking promising research approaches with patient care– from diagnosis to treatment and aftercare. Children suffering from cancer, especially those with no established therapy options, are given an individual therapy plan in the KiTZ, which is created by interdisciplinary expert groups in so-called tumor boards. Many young patients can participate in clinical trials which ensures access to new therapy options. Thus, the KiTZ is a pioneering institution for transferring research knowledge from the laboratory to the clinic.
While the KiTZ focuses on pediatric oncology, the focus of the National Center for Tumor Diseases (NCT), founded in 2004, is adult oncology. Both facilities in Heidelberg are based on the US model of so-called "Comprehensive Cancer Centers" (CCC).
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany's largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.
To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:
National Center for Tumor Diseases (NCT, 6 sites)
German Cancer Consortium (DKTK, 7 sites)
Hopp Children's Cancer Center (KiTZ) Heidelberg
Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
National Cancer Prevention Center (jointly with German Cancer Aid)
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
Heidelberg University Hospital and Faculty of Medicine: Internationally Renowned Patient Care, Research and Teaching
Heidelberg University Hospital (Universitätsklinikum Heidelberg, UKHD) is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University (Medizinische Fakultät Heidelberg, MFHD) belongs to the internationally renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. Heidelberg University Hospital and the Medical Faculty of Heidelberg University employs around 14.500 employees and is committed to providing trainings and qualifications. Every year, around 86,000 patients and more than 1.100.000 outpatient cases are treated in more than 50 clinical departments with almost 2.500 beds.
Together with the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the German Cancer Aid, the UKHD established the first National Center for Tumor Diseases (NCT) in Heidelberg. The goal is to provide care at the highest level as an oncology center of excellence and to rapidly transfer promising approaches from cancer research to the hospital. In addition, the UKHD operates in partnership with the DKFZ and the University of Heidelberg the Hopp Children's Cancer center Heidelberg (KiTZ), a unique and nationally known therapy and research center for oncological and hematological diseases in children and adolescents.
The Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. Currently, there are about 4.000 future physicians studying in Heidelberg.
