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UBC Theses and Dissertations

Exploring the role of mesenchymal progenitors in the medulloblastoma tumor microenvironment Crichlow, Cindy-Lee Maria


Medulloblastoma (MB) is the most prevalent malignant childhood brain tumor which arises in the cerebellum. One molecular subgroup of MB is characterized by mutations in genes in the sonic hedgehog (SHH) signaling pathway, including the receptor Patched 1 (PTCH1). Constitutive activation of the SHH pathway in cerebellar granule cell precursors causes proliferation and cell differentiation failure, leading to tumor formation. While the molecular pathways driving tumor formation are well understood in this subgroup, the MB tumor microenvironment (TME) remains understudied. Mesenchymal progenitors (MPs) are a population of stem-like cells that have been identified as a prominent stromal cell type in a range of primary tumors. MPs are recruited to the TME and contribute to tumor growth and progression through various mechanisms. Previous work by our lab has shown that quiescent MPs are marked by the expression of Hypermethylated in cancer 1 (Hic1). To better understand the role of brain MPs in MB, we utilized an inducible Cre recombinase reporter mouse line to study the contribution of Hic1⁺ MPs to the TME in the Ptch1+/- mouse model of MB. Cerebellar and MB tumor-associated Hic1⁺ MPs were characterized by histological analyses, cell proliferation assays and single-cell RNA sequencing. Lineage tracing revealed that Hic1⁺ MPs are a stable cell population in the cerebellum and contribute dynamically to the MB TME. The large majority of cerebellar and tumor-associated MPs were perivascular and expressed pericyte-associated markers, such as Pdgfrb, Rgs5 and Cspg4. The proliferation rate of tumor-associated MPs was markedly increased compared to cerebellar MPs, indicative of their activation in the MB TME. Single-cell RNA sequencing showed that tumor-associated MPs displayed an altered transcriptomic profile, consistent with an activated phenotype. Furthermore, tumor-associated MPs exhibited upregulation of genes involved in angiogenesis, extracellular matrix reorganization, cell growth and immunomodulation. Overall, Hic1⁺ MPs contribute substantially to the MB tumor stroma and likely provide a microenvironment supportive of tumor growth. A deeper understanding of the role of MPs in the TME has relevance for the development of more targeted treatments for MB, as MPs can potentially be manipulated to slow tumor progression and/or metastasis.

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