Low Levels of Sox2 are required for Melanoma Tumor-Repopulating Cell Dormancy

Jia, Qiong; Yang, Fang; Huang, Wei; Zhang, Yao; Bao, Binghao; Li, Ké; Wei, Fuxiang; Zhang, Cunyu; Jia, Haibo

doi:10.7150/thno.29698

Cited by 23 publications

(16 citation statements)

References 39 publications

(60 reference statements)

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“…For instance, SOX2 has been shown to contribute to melanoma metastasis 35 and to be highly expressed in melanomas compared to nevi 36 . In addition, SOX2 regulates survival, self-renewal, and tumorigenicity of human melanoma-initiating cells 11 , 37 and participates in dormancy regulation of melanoma tumor-repopulating cells 38 . SOX2 has been recently related to the acquisition of an aggressive oxidative tumor phenotype endowed with enhanced drug resistance and metastatic ability 39 .…”

Section: Discussionmentioning

confidence: 99%

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

et al. 2020

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Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

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Section: Discussionmentioning

confidence: 99%

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

et al. 2020

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“…We believe that this may be the main reasons for the inconsistency between PD-1 knockout and knockout. Although knockdown and knockout are often used to verify each other, the results observed by these two methods sometimes still lead to inconsistent conclusions [36].…”

Section: Discussionmentioning

confidence: 99%

PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity

Wei

Luo

Wang

et al. 2019

j. immunotherapy cancer

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Background Blocking programmed death-1 (PD-1) is considered to be a promising strategy to improve T cell function, and this is being explored in many ongoing clinical trials. In fact, our knowledge about PD-1 is primarily based on the results of short-term experiments or observations, but how long-lasting PD-1 blockade can affect T cell function remains unclear. Methods We planned to use shRNA-based gene knockdown technology to mimic long-lasting PD-1 blockade. We constructed PD-1 steadily blocked chimeric antigen receptor modified T (CAR-T) cells, and with these cells we can clearly study the effects of PD-1 knockdown on T cell function. The anti-tumor function, proliferation ability and differentiation status of PD-1 silenced CAR-T cells were studied by in vitro and animal experiments. Results According to short-term in vitro results, it was reconfirmed that the resistance to programmed death-ligand 1 (PD-L1)-mediated immunosuppression could be enhanced by PD-1 blockade. However, better anti-tumor function was not presented by PD-1 blocked CAR-T cells in vitro or in vivo experiments. It was found that PD-1 knockdownmight impair the anti-tumor potential of CAR-T cells because it inhibited T cells’ proliferation activity. In addition, we observed that PD-1 blockade would accelerate T cells’ early differentiation and prevent effector T cells from differentiating into effect memory T cells, and this might be the reason for the limited proliferation of PD-1 silenced CAR-T cells. Conclusion These results suggest that PD-1 might play an important role in maintaining the proper proliferation and differentiation of T cells, and PD-1 silencing would impair T cells’ anti-tumor function by inhibiting their proliferation activity. Electronic supplementary material The online version of this article (10.1186/s40425-019-0685-y) contains supplementary material, which is available to authorized users.

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“…Tumor dormancy is an important process implicated in tumor immune escape and drug resistance (128,129). Jia et al showed that low levels of SOX2 expression are linked to cycle arrest, melanoma cell stemness and tumor dormancy leading long-term tumor survival, and relapse (130).…”

Section: Melanoma Microenvironment Acidification and Its Influence Onmentioning

confidence: 99%

Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

et al. 2020

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Cutaneous melanoma (CM) is a highly aggressive and drug resistant solid tumor, showing an impressive metabolic plasticity modulated by oncogenic activation. In particular, melanoma cells can generate adenosine triphosphate (ATP) during cancer progression by both cytosolic and mitochondrial compartments, although CM energetic request mostly relies on glycolysis. The upregulation of glycolysis is associated with constitutive activation of BRAF/MAPK signaling sustained by BRAF V600E kinase mutant. In this scenario, the growth and progression of CM are strongly affected by melanoma metabolic changes and interplay with tumor microenvironment (TME) that sustain tumor development and immune escape. Furthermore, CM metabolic plasticity can induce a metabolic adaptive response to BRAF/MEK inhibitors (BRAFi/MEKi), associated with the shift from glycolysis toward oxidative phosphorylation (OXPHOS). Therefore, in this review article we survey the metabolic alterations and plasticity of CM, its crosstalk with TME that regulates melanoma progression, drug resistance and immunosurveillance. Finally, we describe hallmarks of melanoma therapeutic strategies targeting the shift from glycolysis toward OXPHOS.

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Low Levels of Sox2 are required for Melanoma Tumor-Repopulating Cell Dormancy

Cited by 23 publications

References 39 publications

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity

Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

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