Genomic dissection of tumor heterogeneity and progression

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The first aim of this project is to use single cell sequencing to understand the complexities of cell types and cell to cell heterogeneity that is present within pediatric solid tumors. In this work, we are focusing on generating comprehensive gene expression profiling of the cells present within tumors that occur in patients with NF1. To date we have collected and analyzed surgical specimens from Plexiform Neurofibromas, Atypical Neurofibromas and Malignant Peripheral Nerve Sheath Tumors. Identification and validation of rare cell types that are found within these tumors is currently underway. In addition, we have developed an algorithm to comprehensively characterize the predicted cell to cell interactions within the tumor using single cell transcriptomic data. In parallel, we are analyzing the circulating tumor DNA present within this patient population using low pass whole genome and capture based sequencing, in an effort to develop an assay that might be used to monitor disease progression within this patient population. The second aim of this work is to develop novel barcoding strategies married with single cell sequencing that can be used in preclinical model systems to model tumor cell resistance and survival. Single cell sequencing has the ability to dissect the gene expression profile of thousands of cells in parallel but is limited in its ability to track populations of cells under a selective pressure. In this review period, we have built a unique barcoding system that allows lentiviral insertion of a unique expressed barcode into individual cells, which can then be used to trace a cell throughout the course of any given therapy. We are currently using this platform to understand the transcriptional dynamics and genes that Ewing Sarcoma cells use to survive treatment with topoisomerase inhibitors.