Abstract
Therapies for medulloblastoma, a highly malignant pediatric brain tumor, often impose debilitating effects on the developing child, highlighting the need for molecularly targeted treatments with reduced toxicity. Therapies aimed at tumor-intrinsic mechanisms have translated to limited success thus far. More effective therapeutic strategies may also need to target elements of the tumor microenvironment. Current understanding about the medulloblastoma microenvironment is limited, particularly its cellular composition. To identify genes and biomarkers that compose the medulloblastoma microenvironment, we performed whole-transcriptome sequencing and bioinformatics analyses of 16 patient-derived orthotopic medulloblastoma xenografts (PDOXs), comprising all four medulloblastoma subgroups and matching primary tumors, as well as early and late passages for some models. PDOXs were generated by intracranial injection of human tumor cells into the brain of NSG-mice. In PDOXs, mouse stroma supports human cancer cells. Therefore, the transcriptome of PDXs is composed of a mixture of human RNAs (deriving from tumor cells) and mouse RNAs (deriving from stroma) and a species-specific alignment approach allows for the simultaneous study of both tumor and microenvironment specific signals. The majority of genes differentially expressed between the primary tumors and PDOXs are significantly down-regulated in the human fraction of PDOX RNA-seq data, while being expressed in the mouse fraction, confirming that the human stroma is replaced by murine stromal cells. As additional proof-of-concept, these down-regulated genes are highly enriched for immune response-related genes and collagens. Expression of various growth factor genes, for example IGF2, known to play a role in medulloblastoma tumorigenesis, appears to be of stromal origin.