CD133+ brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence

Garg, Neha; Bakhshinyan, David; Venugopal, Chitra; Mahendram, Sujeivan; Rosa, David A.; Vijayakumar, Thusyanth; Manoranjan, Branavan; Hallett, Robin; McFarlane, Nicole; Delaney, Kathleen H.; Kwiecień, Jacek M.; Arpin, Carolynn C.; Lai, P-S; Gómez‐Biagi, Rodolfo F.; Ali, Ahmed M.; Araujo, Elvin D. de; Ajani, Olufemi; Hassell, John A.; Gunning, Patrick T.; Singh, Sheila K.

doi:10.1038/onc.2016.235

Cited by 51 publications

(53 citation statements)

References 55 publications

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“…3C ). Further, treatment with the covalent STAT3-specific SH2-domain inhibitor PG-S3-009 (Garg et al, 2017) resulted in DFTD cell-specific killing ( Fig. 3D ) and led to reduced expression of ERBB2 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

Kosack

Wingelhofer

Popa

et al. 2018

Preprint

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1The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil 2 facial tumor disease (DFTD). To unveil the molecular underpinnings of DFTD, we designed an 3 approach that combines sensitivity to drugs with an integrated systems-biology characterization. 4 Sensitivity to inhibitors of the ERBB family of receptor tyrosine kinases correlated with their 5 overexpression, suggesting a causative link. Proteomic and DNA methylation analyses revealed 6 tumor-specific signatures linked to oncogenic signaling hubs including evolutionary conserved 7 STAT3. Indeed, ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. 8 Pharmacological blockade of ERBB signaling prevented tumor growth in a xenograft model and 9 resulted in recovery of MHC class I gene expression. This link between the hyperactive ERBB-10

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Section: Resultsmentioning

confidence: 99%

“…These 41 drugs were re-tested as 8-point dose-response in triplicates on the aforementioned 5 cell lines and cell viability was assessed by CellTiter-Glo as described previously. The STAT3 inhibitor PG-S3-009 (Garg et al, 2017) was tested separately as 5-point dose-response curves in triplicates.…”

Section: Supplemental Experimental Proceduresmentioning

confidence: 99%

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

Kosack

Wingelhofer

Popa

et al. 2018

Preprint

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“…Moreover, the use of mice for MB cell propagation is limited by high costs and the management of high-throughput experiments. To validate the stemness lineage of CSCs from MB cells, these can be characterized by the expression of well know stem cell phenotypic markers [25][26][27][28] that are of special interest in understanding the progression of MB [29,30]. Nevertheless, CSCs enrichment often requires particular culture media and presents several difficulties in the experimental protocols, thus resulting in a time-consuming process and suggesting the need for a better characterization of easily available cell lines.…”

Section: Introductionmentioning

confidence: 99%

Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype

Casciati

Tanori

Manczak

et al. 2020

Cancers

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Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains significant and the long-term adverse effects in survivors are substantial. The fraction of cancer stem-like cells (CSCs) because of their self-renewal ability and multi-lineage differentiation potential is critical for tumor initiation, growth, and resistance to therapies. For the development of new CSC-targeted therapies, further in-depth studies are needed using enriched and stable MB-CSCs populations. This work, aimed at identifying the amount of CSCs in three available human cell lines (DAOY, D341, and D283), describes different approaches based on the expression of stemness markers. First, we explored potential differences in gene and protein expression patterns of specific stem cell markers. Then, in order to identify and discriminate undifferentiated from differentiated cells, MB cells were characterized using a physical characterization method based on a high-frequency dielectrophoresis approach. Finally, we compared their tumorigenic potential in vivo, through engrafting in nude mice. Concordantly, our findings identified the D283 human cell line as an ideal model of CSCs, providing important evidence on the use of a commercial human MB cell line for the development of new strategic CSC-targeting therapies.

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“…MB tumors commonly present deregulation and aberrant expression of AKT and STAT3 and the activation of these pathways are associated with enhanced cellular survival, migration, angiogenesis and resistance to chemotherapeutic agents (Hartmann et al, 2006;Xiao et al, 2015). MB brain tumor-initiating cells expressing CD133 drive recurrence mediated by STAT3 activation (Garg et al, 2017). Thus, the upregulation in STAT3 after anticancer treatment with a TrkB inhibitor suggested by our findings could indicate a compensatory response to counteract the inhibitory effects.…”

Section: Differentiation and Pluripotency Markersmentioning

confidence: 62%

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Thomaz

Pinheiro

Souza

et al. 2019

Preprint

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Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker β-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.

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CD133+ brain tumor-initiating cells are dependent on STAT3 signaling to drive medulloblastoma recurrence

Cited by 51 publications

References 55 publications

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

Human Medulloblastoma Cell Lines: Investigating on Cancer Stem Cell-Like Phenotype

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

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