# Deconstruct tumor microenvironment in medulloblastoma

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $364,837

## Abstract

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.

## Key facts

- **NIH application ID:** 9960601
- **Project number:** 5R01NS097271-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Hui Zong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,837
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960601

## Citation

> US National Institutes of Health, RePORTER application 9960601, Deconstruct tumor microenvironment in medulloblastoma (5R01NS097271-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9960601. Licensed CC0.

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