Redefining the Cellular Architecture of Diffuse Intrinsic Pontine Glioma through Large-Scale Single-cell RNA-seq Analyses
Diffuse intrinsic pontine gliomas (DIPG) are uniformly fatal brain tumors, with a peak incidence in children 6- to 9-years of age. They are inoperable, chemotherapy-resistant and only partly radiosensitive - leading to a bleak median survival of less than ten months after diagnosis. DIPG are a heterogeneous disease containing many diverse cell types and this heterogeneity plays a central role in disease progression and resistance to existing therapies. A key shortcoming for the field is that current genomic analyses are performed in bulk tumors, masking the tumor's precise composition.
Here, I propose to interrogate DIPG's cellular and genetic composition at unprecedented resolution, using single-cell sequencing technologies directly applied to clinical biopsies. I will use the information to reconstruct the cellular and genetic architecture of tumors in patients, as my laboratory has done in adult gliomas. I then propose to leverage these analyses to identify novel candidate target genes and to functionally test our hypotheses using genome-editing technologies in patient-derived DIPG models. This proposed project can be undertaken by our team as we have: a) leading expertise in single-cell genomics; b) established a network of collaborations to gain access to rare DIPG biopsies; c) established patient-derived models; d) developed genome-editing capability. All together they make it possible to systematically define key DIPG vulnerabilities. Successful completion of this work is expected to provide insight into DIPG pathogenesis at unprecedented resolution and to reveal unique tumor dependencies that can be targeted to improve the management of these dismal pediatric malignancies.