Single-Cell CRISPRa Screen to Identify Transcription Factors That Mediate Neuroblastoma Phenotypic Switching and Chemotherapy Drug Resistance
Abstract
The FY20 RCRP Focus Area of this project is to understand the regulatory mechanisms that control neuroblastoma cell plasticity and possibly contribute to chemotherapy resistance. Neuroblastoma is a rare pediatric tumor that accounts for 15% of cancer death in children. The 5-year survival rate of high-risk neuroblastoma patients remains under 50% despite being treated with intensive multimodal therapy. Neuroblastoma shows high cellular heterogeneity and can be classified into adrenergic and mesenchymal tumor cell types that are distinct in their phenotype but can transdifferentiate. Mesenchymal type of neuroblastoma is more resistant to chemotherapy drugs than adrenergic type of neuroblastoma. The mesenchymal neuroblastoma cells are enriched in tumors posttreatment and when patients relapse, which suggests that this phenotypic switching from the adrenergic neuroblastoma to the mesenchymal neuroblastoma contributes to the development of chemotherapy resistance and ultimately, relapse. However, the regulatory mechanisms that control the transdifferentiation of adrenergic and mesenchymal type of neuroblastoma remain unclear. Cell identity or phenotype is determined by transcription factors. Dozens of transcription factors are differentially expressed in adrenergic and mesenchymal types of neuroblastoma cells, which are thought to control the phenotypic switching of neuroblastoma cells; however, it is tedious to test these transcription factors one by one using traditional techniques. This study will use a state-of-the-art approach to identify which transcription factors contribute to the transdifferentiation between the adrenergic and mesenchymal neuroblastoma in a high throughput manner. The discovery of such transcription factors will help to determine how to maintain the adrenergic phenotype of neuroblastoma or differentiate the mesenchymal type of neuroblastoma into adrenergic type of neuroblastoma by controlling the expression of these transcription factors, which will make these cells be more sensitive to the chemotherapy drugs. This research is too basic for immediate clinical application, since transcription factors have been traditionally considered “undruggable.” However, recent preclinical and clinical studies have demonstrated that transcription factors can be targeted indirectly, such as the inhibition of transcription factor-cofactor protein-protein interaction. The advent of targeted protein degradation is a promising approach to direct target transcription factors. Thus, our next goal is to develop a therapeutic strategy to target those critical transcription factors directly or indirectly using preclinical models within 5 years. In summary, the success of this study will broaden our understanding of the molecular mechanisms of transdifferentiation in neuroblastoma and provide the basis for translational approaches to overcome chemoresistance in the treatment of neuroblastoma patients. A similar approach could also be applied to study other types of rare cancer that are resistant to chemotherapy drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110772
Entities
People
- Zhihui Liu
Organizations
- National Cancer Institute
- United States Army