Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications

López-Bertoni, Hernando; Johnson, Allen D.; Rui, Yuan; Lal, Bachchu; Sall, Sophie; Malloy, Maureen A.; Coulter, Jonathan B.; Lugo-Fagundo, Maria; Shudir, Sweta; Khela, Harmon; Caputo, Christopher; Green, Jordan J.; Laterra, John

doi:10.1038/s41392-021-00857-0

Cited by 44 publications

(20 citation statements)

References 63 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, this observed imbalance may be a result of different actions of transcription factors, RNA binding proteins, miRNAs targeting mRNA or post-translational modifications (like phosphorylation, acetylation, glycosylation, etc.). Based on the patient-derived glioma stem cells (GSCs) model, the transcription factor (SOX2)-oncomiR (miR-10b-5p)-TET2 axis was identified, which plays an important role in promoting GBM oncogenesis ( 45 ). However, it is one of many potential mechanisms involved in glioblastoma growth.…”

Section: Discussionmentioning

confidence: 99%

The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas

et al. 2022

View full text Add to dashboard Cite

Gliomas are the most common primary malignant intracranial brain tumors. Their proliferative and invasive behavior is controlled by various epigenetic mechanisms. 5-hydroxymethylcytosine (5-hmC) is one of the epigenetic DNA modifications that employs ten-eleven translocation (TET) enzymes to its oxidation. Previous studies demonstrated altered expression of 5-hmC across gliomagenesis. However, its contribution to the initiation and progression of human gliomas still remains unknown. To characterize the expression profiles of 5-hmC and TET in human glioma samples we used the EpiJET 5-hmC and 5-mC Analysis Kit, quantitative real-time PCR, and Western blot analysis. A continuous decline of 5-hmC levels was observed in solid tissue across glioma grades. However, in glioblastoma (GBM), we documented uncommon heterogeneity in 5-hmC expression. Further analysis showed that the levels of TET proteins, but not their transcripts, may influence the 5-hmC abundance in GBM. Early tumor-related biomarkers may also be provided by the study of aberrant DNA hydroxymethylation in the blood of glioma patients. Therefore, we explored the patterns of TET transcripts in plasma samples and we found that their profiles were variously regulated, with significant value for TET2. The results of our study confirmed that DNA hydroxymethylation is an important mechanism involved in the pathogenesis of gliomas, with particular reference to glioblastoma. Heterogeneity of 5-hmC and TET proteins expression across GBM may provide novel insight into define subtype-specific patterns of hydroxymethylome, and thus help to interpret the heterogeneous outcomes of patients with the same disease.

show abstract

Section: Discussionmentioning

confidence: 99%

The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that SOX2 is related to cell stemness and plays a critical role in the progression, metastasis and chemoresistance of tumor cells. Hernando et al mentioned that SOX2 is responsible for glioblastoma cell stemness and tumor propagation, 33 and elevated SOX2 expression has been linked to malignant cell behavior in lung cancer. 34 , 35 A recent study in prostate cancer cells also point to SOX2 as the main regulator of metabolic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a novel highly malignant lung cancer cell line ZX2021H derived from a metastatic lymph node lesion

et al. 2022

Thoracic Cancer

View full text Add to dashboard Cite

Background Lung cancer is a highly malignant tumor with a poor prognosis. The establishment of faithful ex vivo cell models is essential for investigating the metastatic mechanisms and developing new anticancer agents. In this study, we established and characterized a novel lung cancer cell line derived from metastatic lymph node tissue from a Chinese patient. Methods A primary culture of metastatic lymph node tissue from a patient with lung cancer was used to establish a cell line. The phenotypic characteristics of the cell line were characterized by colony‐formation, CCK8, and Transwell assays, and xenografting. The genetic characteristics were evaluated by chromosome analysis, short tandem repeat (STR) profiling, and quantitative real time‐polymerase chain reaction (qRT‐PCR). Results A novel lung cancer cell line, named ZX2021H, was successfully established from a metastatic lymph node lesion from a lung cancer patient. The cell line exhibited high capacities for proliferation and invasion, as validated by its phenotypic and genetic characteristics. This cell line had a unique STR profile and karyotype analysis revealed numerical and structural chromosome abnormalities. The growth rate of in vivo xenografted tumors established using ZX2021H cells was higher than that using H1299 cells. The cell stemness‐related gene SOX2 was overexpressed in ZX2021 compared with H1299 cells, as determined by qRT‐PCR. Conclusion We successfully established a novel, highly malignant lung cancer cell line, ZX2021H, derived from metastatic lymph node tissue from a Chinese lung cancer patient. This cell line may provide an ideal cell model for further studies of the molecular mechanisms underlying lung cancer metastasis and for the development of new anticancer agents.

show abstract

“…Despite the association between genetic aberrations and cell states in GBM ( 59 ), genomic alterations alone are insufficient to explain the highly adaptive and heterogeneous nature of GSCs ( 60 ). Epigenetic modifications mediate the acquisition of a stem-like state in cancer cells, including GBM, and recent studies have implicated epigenetic variability as a driving force in the adaptation of GBM to external stimuli throughout tumor evolution ( 4 , 12 , 14 – 16 , 60 – 62 ).…”

Section: Contribution Of Gscs To the Immunosuppressive Microenvironme...mentioning

confidence: 99%

“…In particular, Oct4 and Sox2 are sufficient to induce stem cell properties and in vivo tumor-propagating potential in differentiated and non-tumorpropagating GBM cells (12,13). Additionally, our lab has identified multiple mechanisms downstream of Oct4 and Sox2 underlying GSC stemness and tumorigenicity (12)(13)(14)(15)(16)(17). Furthermore, epigenetic modifications mediated by Sox2 and Oct4 have implications in GSC-immune interactions that contribute to an immunosuppressive TME (17).…”

mentioning

confidence: 95%

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

2022

Self Cite

View full text Add to dashboard Cite

Despite its growing use in cancer treatment, immunotherapy has been virtually ineffective in clinical trials for gliomas. The inherently cold tumor immune microenvironment (TIME) in gliomas, characterized by a high ratio of pro-tumor to anti-tumor immune cell infiltrates, acts as a seemingly insurmountable barrier to immunotherapy. Glioma stem cells (GSCs) within these tumors are key contributors to this cold TIME, often functioning indirectly through activation and recruitment of pro-tumor immune cell types. Furthermore, drivers of GSC plasticity and heterogeneity (e.g., reprogramming transcription factors, epigenetic modifications) are associated with induction of immunosuppressive cell states. Recent studies have identified GSC-intrinsic mechanisms, including functional mimicry of immune suppressive cell types, as key determinants of anti-tumor immune escape. In this review, we cover recent advancements in our understanding of GSC-intrinsic mechanisms that modulate GSC-TIME interactions and discuss cutting-edge techniques and bioinformatics platforms available to study immune modulation at high cellular resolution with exploration of both malignant (i.e., GSC) and non-malignant (i.e., immune) cell fractions. Finally, we provide insight into the therapeutic opportunities for targeting immunomodulatory GSC-intrinsic mechanisms to potentiate immunotherapy response in gliomas.

show abstract

Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications

Cited by 44 publications

References 63 publications

The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas

The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas

Establishment and characterization of a novel highly malignant lung cancer cell line ZX2021H derived from a metastatic lymph node lesion

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

Contact Info

Product

Resources

About