Dissertation
SUMOylated Etv1 establishes cancer stem cells that support non-stem cancer cells tumorigenesis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007957
Abstract
The Small Ubiquitin-like Modifier (SUMO) pathway serves as a post-translational regulatory mechanism involved in the maintenance and self-renewal of cancer stem cells/tumor-initiating cells (CSCs/TICs). In this study, we found that SUMO inhibition through genetic and pharmacologic approaches represses mammary oncogenesis and inhibits the function of CSCs. In contrast, SUMO inhibition did not affect the growth or mammosphere formation of normal mammary stem cells, suggesting SUMO-sensitive mechanisms are specific for maintaining the oncogenic CSC/TIC population. Transcriptomic analysis indicates ETS Translocation Variant 1, encoded by Etv1 gene, acts as a SUMO-sensitive transcription factor that drives mammary oncogenesis and cancer progression. Inhibition of SUMOylation resulted in a significant reduction in proliferation and colony formation in vitro and completely blocked the formation of flank xenografts in vivo. Expression of a SUMO-resistant Etv1 protein rescued in vitro growth effects, while the SUMO mimetic Etv1 protein had no effect on restoring proliferation. On the other hand, in vivo xenograft assays demonstrated that SUMO mimetic Etv1 protein efficiently induced tumor formation, whereas SUMO-resistant Etv1 protein was unable to rescue tumorigenesis. Bulk RNA-seq and ChIP-seq analyses revealed distinct gene signatures between SUMO-conjugated Etv1 in stem-like cells and SUMO-unconjugated Etv1 in proliferative, non-tumorigenic cells. Furthermore, we determined that stem-like cells could induce the proliferation of non-stem cells in tumorgenesis. Therefore, we conclude Etv1 acts as a SUMO-sensitive transcription factor that drives a stem cell phenotype necessary for mammary oncogenesis and tumorigenesis, providing potential targets for developing new therapeutic strategies.
Details
- Title: Subtitle
- SUMOylated Etv1 establishes cancer stem cells that support non-stem cancer cells tumorigenesis
- Creators
- Zhijie Li
- Contributors
- Ronald Weigel (Advisor)Adam Dupuy (Committee Member)Eric Taylor (Committee Member)Michael Henry (Committee Member)Robert Cornell (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Cancer Biology)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007957
- Publisher
- University of Iowa
- Number of pages
- xi, 138 pages
- Copyright
- Copyright 2025 Zhijie Li
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Date submitted
- 04/15/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 126-138).
- Public Abstract (ETD)
Although there have been advances in early detection and treatment breakthroughs, breast cancer remains the most common malignancy among women. Cancer stem cells (CSCs) or tumor-initiating cells (TICs), represent a small subset of cells (approximately 1%-2%) within tumors, and play a critical role in breast cancer progression, metastasis, and drug resistance. Several clinical studies have shown that patients with tumors enriched in CSCs/TICs have a worse prognosis, with increased rates of recurrence and metastasis. Therefore, understanding the regulatory mechanisms governing CSCs/TICs can provide valuable insights for developing effective therapies to improve patient outcomes.
In this study, we found the Small Ubiquitin-like Modifier (SUMO) pathway plays an important role in maintaining the CSC/TIC population. Treatment with the SUMO inhibitor anacardic acid significantly delayed tumor formation and reduced the CSC/TIC population. Encouragingly, this drug inhibited the function of CSCs/TICs without affecting healthy stem cells, suggesting it may have a profound impact on tumors while limiting side effects on healthy tissue. Further analysis revealed that SUMOylation promotes cancer initiation and progression through a key transcription factor known as Etv1. Inhibition of SUMOylation reduced cellular behaviors characteristic of the CSC/TIC population, while the expression of SUMO-conjugated Etv1 protein rescued these cellular behaviors. These data suggest Etv1 is a SUMO-sensitive factor promoting breast cancer development, providing a potential target for developing effective Etv1- targeted therapies.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984830826302771
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