Wednesday, April 23, 2025
4/23/2025
Dissecting high-risk cell states in neuroblastoma - PROJECT SUMMARY/ABSTRACT: Relapsed disease is a key challenge in cancer biology and medicine. Cancer cells are dynamic and exist in flexibly interconverting and epigenetically-specified states regulated by master transcription factors (mTFs). These mTFs determine the transcriptome and resultant malignant phenotype, including controlling striking differences in sensitivity to chemotherapies. The presence of cellular heterogeneity within tumors, driven by epigenetic control of cell state is a mechanism by which tumor cells may escape from treatment. This has been challenging to study, since tumors are commonly marked by a high mutational load, which may obscure the contribution of cell state. Intriguingly, the pediatric high-risk tumor neuroblastoma (NB) is a heterogenous and lethal tumor associated with epigenetically-plastic cell states, and is marked by a low mutational burden. This makes NB an ideal system to study the contribution of cell state to chemosensitivity. Our long-term goal is to use epigenomic control of cell state to develop mechanistically-based, targeted cancer therapies. The objective of this proposal is to interrogate how mTFs control cell state and chemosensitivity in NB. Our central hypothesis is that chemoresistance and sensitivity are controlled by the mTFs that establish the NB transcriptome and cell state. This hypothesis is formulated based on preliminary data using new systems including cell state reporters and genome engineering coupled with chemical biology to dissect these flexibly- interconverting cell states, termed the “adrenergic (ADRN)” and “mesenchymal (MES)” – states. The rationale for this work is that the MES and ADRN NB cell states display differential sensitivity to chemotherapies and reflect mechanisms by which NB cells evade conventional therapy, driving lethal tumor relapse. This hypothesis will be tested in two parallel specific aims: 1) Interrogating the transcriptional controllers of the MES NB state and leveraging this for therapeutic benefit; and 2) Dissecting the transcriptional maintenance of the ADRN state. First, we will use our reporters, with gene editing and re-expression models, to determine how candidate mTFs initiate and maintain the MES state. We will identify and interrogate MES-specific catalytic targets, to disrupt this chemoresistant, high-risk state. Second, we will use chemical biology approaches in new models of ADRN NB to dissect how mTFs maintain the ADRN chemosensitive state. Using epigenomics and nascent transcriptomics, we will determine and validate the targets regulated by each mTF that establish chemosensitivity. These approaches are innovative as they use new approaches including cell state reporters and chemical degradation to dissect cell state heterogeneity in NB, to illuminate mechanisms of cell state and chemoresistance control. As a result, we expect to identify new vulnerabilities, thereby achieving new research horizons. This approach is significant because it will expand our understanding of how mTFs control cell state and chemoresistance in NB, and identify new, cell-state-specific vulnerabilities. This has the potential to change management of children with NB, while also impacting our understanding of chemoresistant cell state regulation broadly in cancer.
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