Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

Malta, Tathiane M.; Sokolov, Artem; Gentles, Andrew J.; Burzykowski, Tomasz; Poisson, Laila; Weinstein, John N.; Kamińska, Bożena; Huelsken, Joerg; Omberg, Larsson; Gevaert, Olivier; Colaprico, Antonio; Czerwińska, Patrycja; Mazurek, Sylwia; Mishra, Lopa; Heyn, Holger; Krasnitz, A.; Godwin, Andrew K.; Lazar, Alexander J.; Stuart, Joshua M.; Hoadley, Katherine A.; Laird, Peter W.; Noushmehr, Houtan; Wiznerowicz, Maciej

doi:10.1016/j.cell.2018.03.034

Cited by 1,436 publications

(1,427 citation statements)

References 84 publications

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“…We then related our findings on BRG1‐regulated gene expression in GICs to gene expression patterns of GBM patient tumor specimens in the TCGA database. Among the molecular features defined by the PanCancer Atlas molecular classification , we found that BRG1 gene expression levels were positively correlated to the stemness index defined by mRNA expression patterns (mRNAsi) and to the IFN‐score (Fig. ), which assess the degree of oncogenic dedifferentiation and activation of IFN response pathway, respectively .…”

Section: Resultsmentioning

confidence: 96%

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

et al. 2018

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Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is refractory to existing therapeutic regimens, which reflects the presence of stem-like cells, termed Glioma-Initiating Cells (GICs). The complex interactions between different signaling pathways and epigenetic regulation of key genes may be critical in the maintaining GICs in their stem-like state. Although several signaling pathways have been identified as being dysregulated in GBM, the prognosis of GBM patients remains miserable despite improvements in targeted therapies. In this report, we identified that BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, plays a fundamental role in maintaining GICs in their stem-like state. In addition, we identified a novel mechanism by which BRG1 regulates glycolysis genes critical for GICs. BRG1 downregulates the expression of TXNIP, a negative regulator of glycolysis. BRG1 knockdown also triggered the STAT3 pathway, which led to TXNIP activation. We further identified that TXNIP is an STAT3-regulated gene. Moreover, BRG1 suppressed the expression of interferon-stimulated genes, which are negatively regulated by STAT3 and regulate tumorigenesis. We further demonstrate that BRG1 plays a critical role in the drug resistance of GICs and in GIC-induced tumorigenesis. By genetic and pharmacological means, we found that inhibiting BRG1 can sensitize GICs to chemotherapeutic drugs, temozolomide and carmustine. Our studies suggest that BRG1 may be a novel therapeutic target in GBM. The identification of the critical role that BRG1 plays in GIC stemness and chemosensitivity will inform the development of better targeted therapies in GBM and possibly other cancers. Stem Cells 2018.

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Section: Resultsmentioning

confidence: 96%

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

et al. 2018

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“…Recent studies have shown that chromatin‐modifying enzymes (e.g., KDM family) are sensitive to environmental factors such as metabolic state, hypoxia and stress response, and that these KDM enzymes induce chromatin modifications that regulate genes associated with pluripotency and drug resistance . The resulting methylation and transcriptional patterns have been used to derive predictive “stemness‐index” signatures that correctly classified more aggressive and metastatic tumors . However, whether epigenetic alterations can drive rapid phenotypic state transitions between cancer subpopulations without involvement of mutations is not well studied.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

Wei

et al. 2020

Intl Journal of Cancer

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Highly tumorigenic, drug‐resistant cancer stem‐like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem‐like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem‐like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem‐like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug‐resistant phenotype.

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“…The last two decades of research have harnessed enormous forces to define and deeply characterize the specific population of cancer cells termed cancer stem cells (CSCs). Originally, CSCs were defined as a population with the capability to self‐renew and differentiate, and they are highly responsible for tumor growth and progression . CSCs are endowed with intrinsic resistance to chemo‐ and radiotherapy, possessing a high metastatic potential, and providing tumor relapse after treatment.…”

Section: Mechanisms Providing Stem Cell Self‐renewalmentioning

confidence: 99%

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

et al. 2019

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The tripartite-motif (TRIM) family of proteins represents one of the largest classes of putative single protein RING-finger E3 ubiquitin ligases. The members of this family are characterized by an N-terminal TRIM motif containing one RING-finger domain, one or two zinc-finger domains called B boxes (B1 box and B2 box), and a coiled-coil region.The TRIM motif can be found in isolation or in combination with a variety of C-terminal domains, and based on C-terminus, TRIM proteins are classified into 11 distinct groups.Because of the complex nature of TRIM proteins, they are implicated in a variety of cellular functions and biological processes, including regulation of cell proliferation, cell division and developmental processes, cancer transformation, regulation of cell metabolism, autophagocytosis, modification of chromatin status, regulation of gene transcription, post-translational modifications, and interactions with pathogens. Here, we demonstrate the specific activities of TRIM family proteins that contribute to the cancer stem cell phenotype. A growing body of evidence demonstrates that several TRIM members guarantee the acquisition of stem cell properties and the ability to sustain stem-like phenotype by cancer cells using distinct mechanisms. For other members, further work is needed to understand their full contribution to stem cell self-renewal.Identification of TRIM proteins that possess the potential to serve as therapeutic targets may result in the development of new therapeutic strategies. Finally, these strategies may result in the disruption of the machinery of stemness acquisition, which may prevent tumor growth, progression, and overcome the resistance to anticancer therapies. K E Y W O R D Scancer, pluripotency, RING, self-renewal, stem cells, TRIM

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Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

Cited by 1,436 publications

References 84 publications

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

The role of TRIM family proteins in the regulation of cancer stem cell self-renewal

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