Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells

Man, Jianghong; Yu, Xingjiang; Huang, Haidong; Zhou, Wenchao; Xiang, Chaomei; Huang, Haohao; Miele, Lucio; Liu, Zheng-gang; Bebek, Gürkan; Bao, Shideng; Yu, Jennifer

doi:10.1016/j.stem.2017.10.005

Cited by 146 publications

(189 citation statements)

References 72 publications

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“…It has been proposed that a common gene expression program underpins both cancer and stemness. Consistent with this hypothesis, it has been shown that STAT3 is required to maintain stemness in many different tumors [34,35,[64][65][66][67][68][69][70][71][72][73][74][75][76][77]. At least in breast cancer, a critical mechanism stimulated by STAT3 to regulate stemness involves genes in fatty acid oxidation [72,73] and the ability of STAT3 to adjust the ROS levels produced in mitochondria [73].…”

Section: Reprogramming and Stemnessmentioning

confidence: 90%

STAT3 and STAT5 Activation in Solid Cancers

Igelmann¹,

Neubauer²,

Ferbeyre³

2019

Preprint

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The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between prooncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

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Section: Reprogramming and Stemnessmentioning

confidence: 90%

STAT3 and STAT5 Activation in Solid Cancers

Igelmann¹,

Neubauer²,

Ferbeyre³

2019

Preprint

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“…Huang et al ., found that VASN‐containing exosomes promoted the migration of recipient human umbilical vein endothelial cells (HUVECs) . Recently, a report reveal that VASN is critical to maintaining glioma stem‐like cells in hypoxia . However, the role of VASN in cancer remains enigmatic.…”

Section: Introductionmentioning

confidence: 99%

“…12 Recently, a report reveal that VASN is critical to maintaining glioma stem-like cells in hypoxia. 13 However, the role of VASN in cancer remains enigmatic.…”

Section: Introductionmentioning

confidence: 99%

Sialylation of vasorin by ST3Gal1 facilitates TGF‐β1‐mediated tumor angiogenesis and progression

Yeo

Fan

Lin

et al. 2019

Intl Journal of Cancer

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ST3Gal1 is a key sialyltransferase which adds α2,3‐linked sialic acid to substrates and generates core 1 O ‐glycan structure. Upregulation of ST3Gal1 has been associated with worse prognosis of breast cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In our study, we demonstrated that ST3GAL1 ‐silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF‐β1, as a potential candidate that links ST3Gal1 to angiogenesis. LC‐MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O ‐glycans are sialyl‐3T and disialyl‐T. ST3GAL1 ‐silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF‐β1 by 2‐ to 3‐fold and thereby dampening TGF‐β1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse‐free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence ( p = 0.025, HR = 2.967, 95% CI = 1.14–7.67). Since TGF‐β1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF ‐ β1 upregulates ST3Gal1 to circumvent the negative impact of VASN.

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“…Niches provide exclusive habitat where stem cells propagate continuously in an undifferentiated state through self-renewal 5 . GSCs are dispersed within tumors and methodically enriched in perivascular and hypoxic zones 11,12,13 . GSCs essentially received positive signals from endothelial cells and pericytes, such as ligand/receptor triggers of stemness pathways and adhesion components of the extracellular matrix 13,14,15,16,17 .…”

Section: Introductionmentioning

confidence: 99%

“…GSCs essentially received positive signals from endothelial cells and pericytes, such as ligand/receptor triggers of stemness pathways and adhesion components of the extracellular matrix 13,14,15,16,17 . They are also protected in rather unfavorable conditions where their stemness traits resist hypoxic stress, acidification, and nutrient deprivation 11,12,18 . Recently, it has been suggested that this latter capacity is linked to the function of the RNA binding protein QKI in the down-regulation of endocytosis, receptor trafficking and endo-lysosome-mediated degradation 18 .…”

Section: Introductionmentioning

confidence: 99%

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

Jacobs

André-Grégoire

Maghe

et al. 2019

Preprint

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Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-κB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impaired autophagic flux, and culminates in lysosomalmediated death, concomitantly with mTOR inactivation and dispersion from lysosomes.These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.

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Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells

Cited by 146 publications

References 72 publications

STAT3 and STAT5 Activation in Solid Cancers

STAT3 and STAT5 Activation in Solid Cancers

Sialylation of vasorin by ST3Gal1 facilitates TGF‐β1‐mediated tumor angiogenesis and progression

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

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