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A research collaboration involving Baylor College of Medicine, Texas Children’s Hospital, and the Hospital for Sick Children in Toronto has unveiled a significant discovery regarding medulloblastoma, the most common malignant brain tumor in children. Published in Nature Cell Biology, the study reveals a previously unidentified mechanism that facilitates the tumor’s growth and spread along the leptomeninges, the protective membranes surrounding the brain and spinal cord. The researchers found that metastatic medulloblastoma communicates with leptomeningeal fibroblasts, leading to the recruitment and reprogramming of these cells to foster tumor advancement. This insight raises the possibility of new therapeutic interventions aimed at disrupting this interaction to combat this challenging disease.
Dr. Namal Abeysundara, a postdoctoral fellow in Dr. Michael D. Taylor’s lab at the Arthur and Sonia Labatt Brain Tumor Research Center, emphasized the importance of understanding metastasis, which is the leading cause of morbidity and mortality in children suffering from medulloblastoma. Dr. Taylor, who holds prominent roles at Baylor College of Medicine and Texas Children’s Hospital, serves as the corresponding author for the study.
The researchers aimed to explore the dynamics of how medulloblastoma tumors proliferate on the leptomeninges, with hopes of enhancing treatment strategies to improve survival and quality of life for affected children.
Through detailed analysis of metastatic medulloblastoma cells and accompanying fibroblasts within the leptomeninges, the team discovered a unique set of interactions that support tumor proliferation. Abeysundara stated, “We uncovered a critical role of PDGF, a protein secreted by the tumor cells that draws in leptomeningeal fibroblasts, reprogramming them into meningeal fibroblasts that are specific to tumor activity.”
The researchers noted that these reprogrammed fibroblasts differ significantly from typical fibroblasts, as they actively promote medulloblastoma growth by providing BMP4 and BMP7 proteins, which facilitate the tumor’s colonization and spread.
Abeysundara expressed enthusiasm about the revelation of an intercellular communication pathway centered around PDGF and BMP signaling. This discovery validates the hypothesis that cancer cells and their surrounding microenvironment engage in a complex dialogue, ultimately fostering conditions conducive to leptomeningeal disease.
The study also indicates that targeting the interactions between metastatic tumor cells and the surrounding fibroblasts could impede disease advancement. Remarkably, the researchers demonstrated that blocking the PDGF signal in animal models using a PDGF-R neutralizing antibody led to significant improvements in survival, suggesting that interrupting tumor-microenvironment communications could be an effective treatment approach for affected patients.
This research has broader implications, as Abeysundara pointed out that other cancers, including melanoma, breast, and lung cancers, also metastasize to the leptomeninges. Consequently, the methodologies and insights gleaned from this study may extend to the treatment of various other malignancies.
Dr. Taylor added, “Our investigation revealed a concealed communication network within the brain’s protective structures that facilitates medulloblastoma’s spread. This groundbreaking discovery illustrates the cooperative interactions between tumor and non-tumor cells in establishing an environment that favors tumor proliferation, thereby enriching our understanding of medulloblastoma progression.” He holds the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at the Texas Children’s Cancer and Hematology Center and is affiliated with Baylor’s Dan L Duncan Comprehensive Cancer Center.
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