Date of Award
5-2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Biomedical Sciences
Track
Cancer and Developmental Biology
Research Advisor
Kevin W. Freeman, PhD
Committee
Ankush Gosain, PhD; Liza Makowski, PhD; Susan A. Miranda, PhD; Ramesh Narayanan, PhD
Keywords
Cell identity, Core regulatory circuitries, Neuroblastoma, Super-enhancer, Targeting epigenetics
Abstract
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.
ORCID
https://orcid.org/0000-0001-5259-1293
DOI
10.21007/etd.cghs.2023.0627
Recommended Citation
Aljouda, Nour (https://orcid.org/0000-0001-5259-1293), "TCF4 Is a Key Mediator of Cell Identity and Oncogenesis in Neuroblastoma" (2023). Theses and Dissertations (ETD). Paper 642. http://dx.doi.org/10.21007/etd.cghs.2023.0627.
https://dc.uthsc.edu/dissertations/642
Declaration of Authorship
Supplementary table 1.xlsx (11425 kB)
Supplementary Table 1
supplementary table 2.xlsx (14935 kB)
Supplementary Table 2
supplementary table 3.xlsx (22 kB)
Supplementary Table 3
Supplementary table 4.xlsx (171 kB)
Supplementary Table 4
Supplemntary table 5.xlsx (363 kB)
Supplementary Table 5
Included in
Investigative Techniques Commons, Medical Cell Biology Commons, Medical Genetics Commons, Neoplasms Commons