The knowledge of the pathways and target genes that can drive tumors into less recurrent/progressive and rather sensitive to treatment can be a key for cancer treatment. To achieve this, we need to understand heterogeneity within the cancer cells and the cell clones that survive treatment and/or metastasize. We also need to know the microenvironment and the exchange of signals between the cells within the tumor that are key in driving recurrence/progression. Like most cancers, medulloblastoma tumors are considered heterogeneous within the tumor cell population and the microenvironment. The knowledge of the interactions between the tumor cells and its microenvironment is often critical to uncovering the mechanisms of tumor survival.
We propose single-cell RNA-sequencing (scRNA-seq) to define cells and genes critical for Medulloblastoma recurrence/progression. Single cell technologies have the potential to substantially propel discovery in our understanding of MB cancer biology. Here, we hypothesize that characterization of the cellular and genetic landscape of recurrent/progressive MBs will reveal important cellular relationships supportive of MB growth and ultimately lethal progression. In this proposal, we aim to pilot various single-cell profiling technologies on prospective and biobanked tissue, with the goal to extend the approach to profile recurrence/progressive MBs in order to provide a systemic characterization of tumor cell heterogeneity, and cell-cell interactions between tumor cells and cells of the microenvironment.
What are the goals of this project?
The goals of this project are to generate single cell data for prospective medulloblastoma single/primary tumors and PDX, generate 10X single cell data from tissue in freezing media and to integrate this data with CBTN whole genome sequencing, RNAseq and clinical data.
What is the impact of this project?
Therapy resistance is an unsolved clinical challenge in medulloblastoma medulloblastoma and new strategies to prevent therapy resistance is highly warranted. By using single cell profiling integrated with other omics-approaches and clinical data, we hope to uncover, subpopulations representing MB cells that resist treatment. Ultimately, this would help us to unmask new targets and discover therapies that kill or sensitize cancer resistant cancer cells. If successful, this proposal will determine the full cellular and molecular complexity of medulloblastoma s, and primary mechanism(s) that cause resistance to treatment. These studies leverage a highly unique set of reagents and expertise, and it is likely that this proposal will be very novel and that it will improve long-term survival in children with medulloblastoma .
Why the CBTN request is important to this project?
The ambition reflected in this proposal is a product of robust collaboration across clinical/laboratory/bioinformatics experts within our team, D3b at CHOP and the CBTN . The CBTN has already a larger number of medulloblastoma specimens biobanked that would allow us to profile patient-matched recurrent tumors before and after treatment. Moreover, the scRNA-seq data can be integrated with the CBTN genetic data and will provide to the scientific community a better understanding of medulloblastoma biology
The Children's Brain Tumor Network contributed 17 flash frozen tissue samples and 4 tissue in freezing media samples for single-cell profiling.
- Ninib Baryawno, Project Manager
- Peter Kharchenko, Bioinformatician
- Cecilia Dyberg, molecular biologist
- Manouk Verhoeven, molecular biologist
- Shenglin Mei, Bioinformatician
Ninib Baryawno, PhD
Single-cell technologies, computational modeling and preclinical testing to study the role of the tumor microenvironment in cancer development, tumor cell dissemination and cancer resistance
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinica