Gliomagenesis is orchestrated by the Oct3/4 regulatory network

Игнатова, Т Н; Chaitin, Hersh; Kukekov, Nickolay V.; Suslov, Oleg; Dulatova, Galina; Hanafy, Khalid A.; Vrionis, Frank D.

doi:10.23736/s0390-5616.21.05437-0

Cited by 5 publications

(11 citation statements)

References 29 publications

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“…We have previously optimized the generation of brain tumor spheres with sustained Oct3/4 expression. (15,18) In this study we were able to generate mammary epithelial stem cell aggregated (mammospheres) and veri ed complete and stable expression of Oct3/4 expression using GFP and ow cytometry (Fig. 1, A-B).…”

Section: Discussionmentioning

confidence: 68%

“…Using GFP, positively transfected cells were isolated (Fig. 1A) and using growth conditions speci c for human embryonic stem cells (ESCs) (15,18), GFP(+) and GFP(-) clones were cultured separately in stem cell culture (SCC) medium. Single cells were assessed for their ability to maintain stable expression of the Oct3/4-GFP reporter after replication in 2D culture in normal growth media and in 3D mammospheres (mammary epithelial stem cell aggregates) cultured in SCC media (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Monoclonal Oncosphere Culture System-Stem cell culture (SCC) medium Single-cell suspension from tissue specimens or from cultured cells were prepared according to the methods previously published (Ignatova et al, 2021(Ignatova et al, , 2002. Brie y, cells were plated at a density of 60,000 cells/well 6-well plastic dishes with ultra-low attachment surface (Costar) in DMEM/F12 medium mixed with methylcellulose ( nal concentration 0.8%) and supplemented with progesterone (20nM), putrescine (100mkM), sodium selenite (30nM), transferrin (25mkg/ml), epidermal growth factor (10ng/ml), broblast growth factor (10ng/ml), FGF2 (10ng/ml), and insulin (20mkg/ml).…”

Section: Rna Isolation and Rt-pcr Analyses Of Gene Expressionmentioning

confidence: 99%

“…(14) We have previously demonstrated the key role of Oct3/4 regulatory network in regulating stemness in CSCs and tumor initiation in GBM. (15) The modulation of several genes in the Oct3/4 pathway was associated with epigenetically directing oncogenic reprogramming, cellular physiology, and metabolism during tumor development in cervical and gastric cancers. (16,17) Our current study aimed to assess the role of transcription factors including ONSS and other related genes in the Oct3/4 network to regulate breast cancer stem cells and drive their organ-speci c metastatic potential using the MDA-MB-231 breast cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

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Malignant potential of breast cancer stem cells is associated with environment- dependent upregulation of the Oct3/4 network

Rajan

Krutilina

Игнатова

et al. 2022

Preprint

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Introduction: The pioneer transcriptional factors (PTFs) of the Oct3/4 network including Oct3/4, Nanog, Sox2, Sall4 (ONSS), have been associated with breast cancer. Regulation of ONSS and other factors in this network were assessed for their role in malignancy. Methods: Triple negative breast cancer cell line (MDA-MB-231) transfected with human Oct3/4-GFP promoter was sorted using FACS. Differentially expressed genes (DEGs) were identified using qPCR and microarray. 3D mammospheres (CSC) from Oct3/4(+) cells were assessed for stable Oct3/4 expression. Tumor seeding and lung metastatic potential of Oct3/4(+) cells were assessed in immunocompromised mice. DEGs in the tumors were assessed with respect to implanted tissue (SQ, lungs or brain), recurrence, and metastases. Expression of CD44+/CD24- was evaluated using flow cytometry. Resistance of Oct3/4(+) cells to paclitaxel was assessed using MTS assay. Results: Oct3/4-GFP expression was stable in mammospheres. Oct3/4(+) cells showed 25 DEGs and significant resistance to paclitaxel when compared to non-transfected cells. Upregulated growth and developmental genes included Gata6, FoxA2, Sall4, Zic2, H2afJ, Stc1 and Bmi1. The Oct3/4(+) cells also showed enhanced tumorigenic potential and aggressive growth in immunocompromised mice. Additionally, this modulated transcriptome of the Oct3/4 (+) cells showed further upregulation of several genes in metastatic lung lesions in mice (> 5 fold) compared to orthotopic tumors including Oct4A, Bmi1, Ezh2, Klf5, Hox7B, Gja1, Stc1, Amigo2 and Dkk1. Serially re-implanting tumors in mice as a model of recurrence and metastasis highlighted Sall4, c-Myc, Mmp1, Mmp9 and Dkk1 genes in maintaining an upregulated expression specifically in metastatic lesions and a 2-fold higher expression of stem cell phenotype markers (CD44+/CD24-). Overall Oct3/4 expression in tumors in lungs, brain and metastases were significantly higher than orthotopic mammary fat pad tumors. Additionally, the transcriptome was most upregulated in brain except for Gja1 and H2faJ, indicating tissue-specific regulation of this transcriptome. Conclusion: ONSS and other Oct3/4 related factors may drive the differentiation and maintenance of breast cancer stem cells and may promote their tumorigenic potential and resistance to drugs such as paclitaxel. However, there is tissue-specific heterogeneity in the differential upregulation of this transcriptome as well stemness phenotype of tumors in these tissues.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Rna Isolation and Rt-pcr Analyses Of Gene Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Malignant potential of breast cancer stem cells is associated with environment- dependent upregulation of the Oct3/4 network

Rajan

Krutilina

Игнатова

et al. 2022

Preprint

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“…Nevertheless, GSCs are responsible, in the vast majority of cases, for tumor recurrence and resistance to therapies. GSCs recapitulate most of the molecular characteristics of pluripotent stem cells, including the activation of stem factors such as Oct4, KLF4, Nanog, and SOX2, which constitute a self-fueled transcriptional circuit [ 84 , 85 , 86 ], and the Wnt/β-catenin, Sonic Hedgehog (Shh), and Notch pathways [ 87 , 88 , 89 ], granting self-renewal. They also possess the capacity to undergo asymmetric cell division, giving rise to both proliferating, self-renewing stem cells and to differentiated cells with low tumorigenic potential, which enrich the bulk of tumors.…”

Section: Glioblastoma Multiformementioning

confidence: 99%

The “Superoncogene” Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme

Cencioni

Scagnoli

Spallotta

et al. 2023

IJMS

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The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.

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Gliomas: a reflection of temporal gliogenic principles

Sojka,

Sloan

2024

Commun Biol

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The hijacking of early developmental programs is a canonical feature of gliomas where neoplastic cells resemble neurodevelopmental lineages and possess mechanisms of stem cell resilience. Given these parallels, uncovering how and when in developmental time gliomagenesis intersects with normal trajectories can greatly inform our understanding of tumor biology. Here, we review how elapsing time impacts the developmental principles of astrocyte (AS) and oligodendrocyte (OL) lineages, and how these same temporal programs are replicated, distorted, or circumvented in pathological settings such as gliomas. Additionally, we discuss how normal gliogenic processes can inform our understanding of the temporal progression of gliomagenesis, including when in developmental time gliomas originate, thrive, and can be pushed towards upon therapeutic coercion.

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Gliomagenesis is orchestrated by the Oct3/4 regulatory network

Cited by 5 publications

References 29 publications

Malignant potential of breast cancer stem cells is associated with environment- dependent upregulation of the Oct3/4 network

Malignant potential of breast cancer stem cells is associated with environment- dependent upregulation of the Oct3/4 network

The “Superoncogene” Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme

Gliomas: a reflection of temporal gliogenic principles

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