Abstract
Medulloblastoma (MB) is a paediatric cancer of the cerebellum that can develop cerebellar and leptomeningeal metastases. Local brain tissue infiltration, the underlying cause of metastasis and relapse, remains unexplored. We developed a novel approach to investigate tissue infiltration of MB using organotypic cerebellum slice culture (OCSC). We show that cellular and structural components of cerebellar tissue in OCSCs are maintained for up to 30 days ex vivo, and that OCSCs foster tumour growth and cell proliferation. Using cell-based models of sonic hedgehog (SHH) and group 3 (G3) MB, we quantified tumour growth and infiltration and determined the morphological characteristics of the infiltrating cells. We observed basal levels of dissemination occurring in both subgroups with cells migrating either individually or collectively as clusters. Collective cerebellar tissue infiltration of SHH MB cells was further enhanced by EGF but not HGF, demonstrating differential tumour cell responses to microenvironmental cues. We found G3 cells to be hyper proliferative and observed aggressive tumour expansion even in the absence of exogenous growth factors. Our study thus provides unprecedented insights into brain tissue infiltration of SHH and G3 MB cells and reveals the cellular basis of the tumour progressing functions of EGF in SHH MB.
Highlights
Medulloblastoma (MB) is a paediatric cancer of the cerebellum that can develop cerebellar and leptomeningeal metastases
In order to set up the ex vivo model, cerebella were dissected from mice pups at postnatal day (PND) 8–10, sliced and put in culture under physiological conditions (Fig. 1A)
We demonstrated that the host cerebellum tissue and the co-cultured tumour cells survive for up to 30 days ex vivo
Summary
Medulloblastoma (MB) is a paediatric cancer of the cerebellum that can develop cerebellar and leptomeningeal metastases. Accurate orthotopic implantation is a technically challenging approach and screening of therapeutic targets and testing the efficacy of potential drugs is rather inefficient and very costly using these models This calls for the development of an appropriate system that would use a normal brain component such as the cerebellum along with the MB tumour and bridge the current gap between in vitro and in vivo research. Still largely unresolved questions are which of the metastasis-associated genetic events encode the cellular functions that drive dissemination away from the primary tumour and whether specific cellular or topological characteristics of the cerebellar microenvironment facilitate tissue infiltration This is relevant in light of the consensus reached recently on the high risk associated with metastatic MB, in particular for SHH and group 3 MB21
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