Tumor is a living organ. Effective cancer treatment must deal with not only the genetic alterations within tumor cells, but also the supportive tumor microenvironment (TME). Our lab studies the roles of TME in medulloblastoma, the most common malignant pediatric brain tumor. Although improved radiation and chemotherapy greatly boosted patient survival rates, traditional treatment often leads to devastating side effects in young children. Since aberrant sonic hedgehog (Shh) signaling in granule neuron precursors (GNPs) is a common cause of desmoplastic medulloblastoma, inhibitors of the Shh pathway that can effectively kill tumor cells have been developed. However, toxicity in patients and mutations that resist these inhibitors greatly reduced their clinical applicability. To identify additional mechanisms that could alleviate that problem, we set out to investigate mechanisms of tumor-TME interactions with mouse genetic models and found the prominent presence of astrocytes and tumor-associated microglia/macrophages (TAMs). We also screened a panel of growth factors with qRT-PCR, and found that IGF1 fits the bill as a TME factor since it is consistently elevated in the tumor mass, but is absent from tumor GNPs. Further studies showed that IGF1 greatly promoted proliferation of tumor GNPs in culture, and that the loss of IGF1R specifically in GNPs led to halted tumor progression. Using in situ hybridization, we pinpointed TAMs but not other cell types as the IGF1-secreting TME cell type. Co-culture of tumor cells with TAMs led to sustained proliferation, an effect abrogated by the IGF1-blocking agent. Finally, we found that IL-4 is produced by astrocytes in the TME, which is known to promote IGF1 expression in microglia/macrophages. In conclusion, we have identified a TME network that centered on IGF1 signaling to promote medulloblastoma progression. Based on our preliminary findings, we hypothesize that disrupting the TME-tumor crosstalk along the IGF1 axis should be an effective therapeutic strategy for medulloblastoma. In this grant application, we propose to test our hypothesis by directly inhibiting IGF1R signaling in tumor cells, by removing IGF1 from TAMs, and by cutting off the IL-4 signaling from astrocytes to TAMs thus reduce their IGF1 production. We have assembled a team of experts in mouse genetics, immunology, and human brain tumor pathology, and are confident that our studies will contribute to the development of highly effective, novel treatment strategies. In the long term, the principles that emerge from our studies should not only benefit medulloblastoma patients, but also provide a basis for innovative therapies for other neurological diseases.

Public Health Relevance

Medulloblastoma is the most common pediatric malignant brain tumor, and current treatment methods often lead to severe side effects on brain development in young patients. Our proposed work will examine the critical contributions of tumor microenvironment to tumor initiation and progression. Findings from our studies would help guide the development of novel, highly specific therapeutic strategies that undermine tumor by destabilize its environment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Fountain, Jane W
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University of Virginia
Schools of Medicine
United States
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