TCF4 Is a Key Mediator of Cell Identity and Oncogenesis in Neuroblastoma

<p>Neuroblastomas (NB) are embryonal childhood tumors that derive from the multipotent neural crest cells (NCCs) of the peripheral nervous system. NB accounts for more than 15% of all childhood cancer-related deaths. Despite the most intensive multimodal therapy, more than 50% of patients with high-risk NB relapse with often fatal, resistant disease. Novel therapies are desperately needed to improve cure rates. Previous studies proposed that the deregulation of normal neural crest developmental programs contributes to NB oncogenesis by retaining the highly migratory and proliferative traits of NCCs. Thus, activation or repression of neural crest developmental pathways have been implicated in NB pathogenesis. Recent data reported two identities in neuroblastoma cell lines: one establishing a more proliferative adrenergic (ADRN) cell state and a second establishing a more invasive, therapy-resistant mesenchymal (MES) cell state. Super-enhancer-associated transcription factor (TF) networks define cell identities in neuroblastoma (NB). Dysregulation of these TFs contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report the bHLH transcription factor TCF4 (E2-2) is a critical NB dependency gene that significantly contributes to these identity states through its heterodimerization with cell identity specific bHLH TFs. Mechanistically, we show that TCF4 promotes cell proliferation through direct transcriptional regulation of a MYC/MYCN oncogenic program. To identify potential therapeutic vulnerabilities, we characterized the TCF4 regulatory interactome and identified multiple epigenetic factors including HDACs and KDM1A. We determined that inhibitors to both HDACs and KDM1A, which often form complexes together, reduce TCF4 protein stability. Our work suggests that loss of TCF4 protein expression is an important biological readout for determining the efficacy of these epigenetic inhibitors in treating patients and could lead to improved patient outcomes.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year dc:date.available

2023

Author dc:creator

• Aljouda, Nour

Contributors dc:contributor

• Kevin W. Freeman, PhD

• Cell identity
• Core regulatory circuitries
• Neuroblastoma
• Super-enhancer
• Targeting epigenetics
• Analytical, Diagnostic and Therapeutic Techniques and Equipment
• Diseases
• Investigative Techniques
• Medical Cell Biology
• Medical Genetics
• Medical Sciences
• Medicine and Health Sciences
• Neoplasms

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/642

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1642