Autophagic homeostasis is required for the pluripotency of cancer stem cells

Sharif, Tanveer; Martell, Emma; Dai, Cathleen; Kennedy, Barry E.; Murphy, Patrick J.; Clements, Derek R.; Kim, Youra; Lee, Patrick W.K.; Gujar, Shashi

doi:10.1080/15548627.2016.1260808

Cited by 116 publications

(110 citation statements)

References 48 publications

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“…Cells from cluster 4 (about 1.5% of the population) displayed slower proliferation rates, increased ALDH activity, higher autolysosomes load and increased resistance to carboplatin (Fig H). Such phenotypic signature is typically attributed to cancer cells with stem‐like characteristics(Ma & Allan, ; Vitale et al , ; Tomita et al , ; Peng et al , ; Sharif et al , ; Boya et al , ; Nazio et al , ). Within the largest cluster of clones (cluster 1), sensitivity to carboplatin showed a moderate correlation with proliferation rate (Fig EV6B).…”

Section: Resultsmentioning

confidence: 99%

Improved detection of differentially represented DNA barcodes for high‐throughput clonal phenomics

Akimov

Bulanova

Timonen

et al. 2020

Molecular Systems Biology

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Cellular DNA barcoding has become a popular approach to study heterogeneity of cell populations and to identify clones with differential response to cellular stimuli. However, there is a lack of reliable methods for statistical inference of differentially responding clones. Here, we used mixtures of DNA‐barcoded cell pools to generate a realistic benchmark read count dataset for modelling a range of outcomes of clone‐tracing experiments. By accounting for the statistical properties intrinsic to the DNA barcode read count data, we implemented an improved algorithm that results in a significantly lower false‐positive rate, compared to current RNA‐seq data analysis algorithms, especially when detecting differentially responding clones in experiments with strong selection pressure. Building on the reliable statistical methodology, we illustrate how multidimensional phenotypic profiling enables one to deconvolute phenotypically distinct clonal subpopulations within a cancer cell line. The mixture control dataset and our analysis results provide a foundation for benchmarking and improving algorithms for clone‐tracing experiments.

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Section: Resultsmentioning

confidence: 99%

Improved detection of differentially represented DNA barcodes for high‐throughput clonal phenomics

Akimov

Bulanova

Timonen

et al. 2020

Molecular Systems Biology

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“…NAMPT overexpression in experimental models of glioblastoma resulted in a cellular phenotype consistent with that of a cancer stem-like cell (126), while pharmacological and genetic inhibition of NAMPT decreased the ability of glioblastoma stem cells to self-renew and form in vivo tumors (131). In one study, the loss of cancer stem cell pluripotency upon inhibition of NAMPT was the result of an excess of autophagy, a well-described consequence of NAMPT inhibition (15,58,64,121,(132)(133)(134)(135), which disrupted the maintenance of cancer cell stemness (136). NAMPT inhibition has also been shown to reverse the ability of cancer cells to dedifferentiate (137).…”

Section: Epithelial-mesenchymal Transformation and Stemnessmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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“…Regarding cancer therapy, strategies of both stimulation and inhibition of autophagy have been considered. For example, the silencing of ATG5 and ATG12 could inhibit autophagy, consequently attenuating CSC properties [6,80]. The blockage of autophagic flux leads to cell death by augmenting stress-activated proteins, such as JNK and p38 [81].…”

Section: Dual Roles Of Autophagy In Cancermentioning

confidence: 99%

“…Cancer stem cells (CSCs) are known to be resistant to cancer treatments due to several features, such as self-renewal potential, activation of the DNA damage response, and high levels of drug transporter [4]. Autophagy is also known to support the properties of CSCs [5,6]. Additionally, epithelial-mesenchymal transition (EMT) has been revealed 2.3.1.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

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Autophagic homeostasis is required for the pluripotency of cancer stem cells

Cited by 116 publications

References 48 publications

Improved detection of differentially represented DNA barcodes for high‐throughput clonal phenomics

Improved detection of differentially represented DNA barcodes for high‐throughput clonal phenomics

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

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