CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells

Johansson, Elinn; Grassi, Elisa; Pantazopoulou, Vasiliki; Tong, Bei; Lindgren, David; Berg, Tracy J.; Pietras, Elin J.; Axelson, Håkan; Pietras, Alexander

doi:10.1016/j.celrep.2017.07.049

Cited by 95 publications

(94 citation statements)

References 31 publications

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“…1b). Co-staining against HIF-1α, a hypoxia marker, and CD44, a marker previously used to define perivascular and perinecrotic tumor areas [20], revealed that DLK1 localized prevalently in perivascular and hypoxic niches, with previously unreported nuclear localization specifically in these areas ( Fig. 1c-h).…”

Section: Dlk1 Is Overexpressed In Gbm and Its Subcellular Localizatiomentioning

confidence: 61%

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Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

2020

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Glioblastoma multiforme is characterized in part by severe hypoxia associated with tumor necrosis. The cellular response to hypoxia can influence several properties of tumor cells associated with aggressive tumor growth, including metabolic adaptations and tumor cell migration and invasion. Here, we found that Delta Like Non-Canonical Notch Ligand 1 (DLK1) expression was elevated as compared with normal brain in a genetically engineered mouse model of glioma, and that DLK1 expression increased with tumor grade in human glioma samples. DLK1 expression was highest in hypoxic and perivascular tumor areas, and we found that hypoxia induced the release and nuclear translocation of an intracellular fragment of DLK1 in murine glioma as well as in human glioma cultures. Release of the intracellular fragment was dependent on ADAM17 and Hypoxia-inducible Factor 1alpha and 2alpha (HIF-1alpha/HIF-2alpha), as ADAM17 inhibitors and HIF1A/HIF2A siRNA blocked DLK1 cleavage. Expression of a cleavable form of DLK1 amplified several hypoxia-induced traits of glioma cells such as colony formation, stem cell marker gene expression, a PI3K-pathway-mediated metabolic shift, and enhanced invasiveness. Effects of DLK1 were dependent on DLK1-cleavage by ADAM17, as expression of non-cleavable DLK1 could not replicate the DLK1-induced hypoxic phenotype. Finally, forced expression of DLK1 resulted in more invasive tumor growth in a PDGFB-induced glioma mouse model without affecting overall survival. Together, our findings suggest a previously undescribed role for DLK1 as an intracellular signaling molecule.

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Section: Dlk1 Is Overexpressed In Gbm and Its Subcellular Localizatiomentioning

confidence: 61%

“…Murine gliomas were generated using RCAS/tv-a to overexpress PDGFB and induce p53/PTEN loss in Nestinexpressing cells of Nestin-tv-a (Ntv-a) mice [19,20]. Western blots revealed enhanced DLK1 expression in tumors compared with surrounding normal brain (Fig.…”

Section: Dlk1 Is Overexpressed In Gbm and Its Subcellular Localizatiomentioning

confidence: 99%

Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

2020

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“…Thus, in thyroid carcinoma cells, which harbor activated RET/PTC, RAS, or BRAF, CD44-ICD accumulated, a blockade of γ-secretase blunting CD44 processing (De Falco et al, 2012). In mammary cancer the CD44-ICD is engaged in EMT-related transcription factor expression and nuclear translocation, particularly of Oct4 and Sox2 (Cho et al, 2015) In glioma CIC, the CD44-ICD is engaged in hypoxic state maintenance via binding HIF2α, which enhances HIF target gene activation at perivascular oxygen tension (Johansson et al, 2017). Thyroid carcinoma cells harboring activated oncogenes exhibited CD44-ICD accumulation.…”

Section: Linking Cd44/cd44v6 Activities To Cic Featuresmentioning

confidence: 99%

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Wang

Zhao

Hackert

et al. 2018

Front. Cell Dev. Biol.

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Metastasis is the leading cause of cancer death, tumor progression proceeding through emigration from the primary tumor, gaining access to the circulation, leaving the circulation, settling in distant organs and growing in the foreign environment. The capacity of a tumor to metastasize relies on a small subpopulation of cells in the primary tumor, so called cancer-initiating cells (CIC). CIC are characterized by sets of markers, mostly membrane anchored adhesion molecules, CD44v6 being the most frequently recovered marker. Knockdown and knockout models accompanied by loss of tumor progression despite unaltered primary tumor growth unraveled that these markers are indispensable for CIC. The unexpected contribution of marker molecules to CIC-related activities prompted research on underlying molecular mechanisms. This review outlines the contribution of CD44, particularly CD44v6 to CIC activities. A first focus is given to the impact of CD44/CD44v6 to inherent CIC features, including the crosstalk with the niche, apoptosis-resistance, and epithelial mesenchymal transition. Following the steps of the metastatic cascade, we report on supporting activities of CD44/CD44v6 in migration and invasion. These CD44/CD44v6 activities rely on the association with membrane-integrated and cytosolic signaling molecules and proteases and transcriptional regulation. They are not restricted to, but most pronounced in CIC and are tightly regulated by feedback loops. Finally, we discuss on the engagement of CD44/CD44v6 in exosome biogenesis, loading and delivery. exosomes being the main acteurs in the long-distance crosstalk of CIC with the host. In brief, by supporting the communication with the niche and promoting apoptosis resistance CD44/CD44v6 plays an important role in CIC maintenance. The multifaceted interplay between CD44/CD44v6, signal transducing molecules and proteases facilitates the metastasizing tumor cell journey through the body. By its engagement in exosome biogenesis CD44/CD44v6 contributes to disseminated tumor cell settlement and growth in distant organs. Thus, CD44/CD44v6 likely is the most central CIC biomarker.

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“…In terms of differentially active proteins, these cells appear to phenocopy myeloid-derived suppressor cells (MDSCs), which accumulate in solid tumors and represent major immunosuppression modulators. Specifically, CEBPE is an established, myeloid-specific isoform and a critical factor for immature myeloid precursor differentiation (Akagi et al, 2010; Bedi et al, 2008; Rodriguez-Barrueco et al, 2015); TNFRSF1A, a prototypical TNF-alpha receptor, and TNF-alpha represent a critical checkpoint in MDSCs generation (Raveney et al, 2010; Sade-Feldman et al, 2013; Zhao et al, 2012); CD44 , a maker of normal myelopoeisis and acute myeloid leukemia (Charrad et al, 1999; Jin et al, 2006) is expressed in mesenchymal-like GBM cells (Johansson et al, 2017; Mooney et al, 2016); CXCL14, is also an established MDSC marker (Shurin et al, 2005). Independently, aberrant activation of PDPN, LGALS1, and CDKN1A is consistent with the invasive phenotype presented by these cells (Ilarregui et al, 2009; Krishnan et al, 2018; Okuma et al, 2017; Shiina et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

Ding

Burgenske

Zhao

et al. 2019

Preprint

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Glioblastoma heterogeneity and plasticity remain controversial, with proposed subtypes representing the average of highly heterogeneous admixtures of independent transcriptional states. Single-cell, protein-activity-based analysis allowed full quantification of >6,000 regulatory and signaling proteins, thus providing a previously unattainable single-cell characterization level. This helped identify four novel, molecularly distinct subtypes that successfully harmonize across multiple GBM datasets, including previously published bulk and single-cell profiles and single cell profiles from seven orthotopic PDX models, representative of prior subtype diversity. GBM is thus characterized by the plastic coexistence of single cells in two mutually-exclusive developmental lineages, with additional stratification provided by their proliferative potential. Consistently, all previous subtypes could be recapitulated by single-cell mixtures drawn from newly identified states. Critically, drug sensitivity was predicted and validated as highly state-dependent, both in single-cell assays from patient-derived explants and in PDX models, suggesting that successful treatment requires combinations of multiple drugs targeting these distinct tumor states. Significance We propose a new, 4-subtype GBM classification, which harmonizes across bulk and single-cell datasets. Single-cell mixtures from these subtypes effectively recapitulate all prior classifications, suggesting that the latter are a byproduct of GBM heterogeneity. Finally, we predict single-cell level activity of three clinically-relevant drugs, and validate them in patient-derived explant.

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CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells

Cited by 95 publications

References 31 publications

Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

Hypoxia-induced release, nuclear translocation, and signaling activity of a DLK1 intracellular fragment in glioma

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression

Single-cell based elucidation of molecularly-distinct glioblastoma states and drug sensitivity

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