ARNT-dependent HIF-2 transcriptional activity is not sufficient to regulate downstream target genes in neuroblastoma

Persson, C.; Stedingk, Kristoffer von; Fredlund, Elina; Bexell, Daniel; Påhlman, Sven; Wigerup, Caroline; Mohlin, Sofie

doi:10.1016/j.yexcr.2020.111845

Cited by 29 publications

(40 citation statements)

References 25 publications

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“…Error bars represent SEM, n ≥ 3 biologically independent replicates for each time point HIF-2α expression at lowered oxygen concentrations ( Figure 1G). Together with previous data on these antibodies, 6,9,15,16 these results ensure antibody specificity.…”

Section: Hif-2α Is Expressed In Migratory Trunk Neural Crest Cells supporting

confidence: 85%

“…[6][7][8] Accordingly, HIF-2α can become abnormally stabilized at physiological oxygen tensions (5% O 2 ) in vitro. 6,9 Previous studies in chick, quail and Xenopus embryos have shown that related HIF1A (encoding HIF-1α) and ARNT (encoding HIF-1β, transcriptional binding partner of both HIF-α isoforms) genes co-localize and are ubiquitously expressed within the developing embryo, as investigated at time points up to HH14 (HH stages in chick embryos). [10][11][12][13][14] EPAS1 (encoding HIF-2α) is however expressed in a more distinct pattern and in tissues not expressing HIF1A (extraembryonic and endothelial cells).…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia inducible factor‐2α importance for migration, proliferation, and self‐renewal of trunk neural crest cells

Niklasson

Fredlund

Monni

et al. 2020

Developmental Dynamics

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Background: The neural crest is a transient embryonic stem cell population. Hypoxia inducible factor (HIF)-2α is associated with neural crest stem cell appearance and aggressiveness in tumors. However, little is known about its role in normal neural crest development. Results: Here, we show that HIF-2α is expressed in trunk neural crest cells of human, murine, and avian embryos. Knockdown as well as overexpression of HIF-2α in vivo causes developmental delays, induces proliferation, and selfrenewal capacity of neural crest cells while decreasing the proportion of neural crest cells that migrate ventrally to sympathoadrenal sites. Reflecting the in vivo phenotype, transcriptome changes after loss of HIF-2α reveal enrichment of genes associated with cancer, invasion, epithelial-to-mesenchymal transition, and growth arrest. Conclusions: Taken together, these results suggest that expression levels of HIF-2α must be strictly controlled during normal trunk neural crest development and that dysregulated levels affects several important features connected to stemness, migration, and development. K E Y W O R D S embryogenesis, HIF-2α, migration, neural crest, stem cells, trunk neural crest Camilla U. Niklasson and Elina Fredlund contributed equally to this work.

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Section: Hif-2α Is Expressed In Migratory Trunk Neural Crest Cells supporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Hypoxia inducible factor‐2α importance for migration, proliferation, and self‐renewal of trunk neural crest cells

Niklasson

Fredlund

Monni

et al. 2020

Developmental Dynamics

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“…As HIF-2a is a known driver of stem cell characteristics in glioma and other tumor forms [31 , 23 , [32] , [33] , [34] ], we next tested whether effects of DLK1 on glioma cell behavior were mediated by HIF-2a. The treatment with the specific HIF-2a inhibitor PT2385 at concentrations with significant effects on HIF-2a protein [35 , 36] (Supplementary Fig. 4) was able to revert the DLK1-induced increase in hypoxia response ( Figure 6 A).…”

Section: Resultsmentioning

confidence: 92%

Niche-derived soluble DLK1 promotes glioma growth

et al. 2020

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“…PT2385 and its analog PT2399 have shown great efficacy in preclinical models of clear cell renal cell carcinoma (ccRCC) [84,86], which leads to phase 1 clinical trial of this molecule in patients of advanced ccRCC (NCT02293980). The effect of PT2385 has been evaluated in only one study in neuroblastoma and the study has shown that PT2385 did not affect the cellular response to chemotherapy in neuroblastoma PDX model [87]. However, recently no clinical trial of this drug is in place for neuroblastoma patients, but this drug can be evaluated in NB clinical trials, based on the efficacy of this drug in ccRCC and recurrent glioblastoma.…”

Section: Targeting Hypoxiamentioning

confidence: 99%

Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions

Joshi

2020

Cancers

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Neuroblastoma (NB) is the most common pediatric tumor malignancy that originates from the neural crest and accounts for more than 15% of all the childhood deaths from cancer. The neuroblastoma cancer research has long been focused on the role of MYCN oncogene amplification and the contribution of other genetic alterations in the progression of this malignancy. However, it is now widely accepted that, not only tumor cells, but the components of tumor microenvironment (TME), including extracellular matrix, stromal cells and immune cells, also contribute to tumor progression in neuroblastoma. The complexity of different components of tumor stroma and their resemblance with surrounding normal tissues pose huge challenges for therapies targeting tumor microenvironment in NB. Hence, the detailed understanding of the composition of the TME of NB is crucial to improve existing and future potential immunotherapeutic approaches against this childhood cancer. In this review article, I will discuss different components of the TME of NB and the recent advances in the strategies, which are used to target the tumor microenvironment in neuroblastoma.

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ARNT-dependent HIF-2 transcriptional activity is not sufficient to regulate downstream target genes in neuroblastoma

Cited by 29 publications

References 25 publications

Hypoxia inducible factor‐2α importance for migration, proliferation, and self‐renewal of trunk neural crest cells

Hypoxia inducible factor‐2α importance for migration, proliferation, and self‐renewal of trunk neural crest cells

Niche-derived soluble DLK1 promotes glioma growth

Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions

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