Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment

Shu, Shin La; Yang, Yunchen; Allen, Cheryl; Maguire, Orla; Minderman, Hans; Sen, Arindam; Ciesielski, Michael; Collins, Katherine A.; Bush, Peter J.; Singh, Prashant; Wang, Xue; Morgan, Martin; Qu, Jun; Bankert, Richard B.; Whiteside, Theresa L.; Wu, Yun; Ernstoff, Marc S.

doi:10.1038/s41598-018-31323-7

Cited by 139 publications

(142 citation statements)

References 63 publications

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“…The delivery of GLUT1 and PKM2 by hEVs could thus lead to a glycolysis increase in the recipient cells [62]. Another study by Shu et al demonstrated that melanoma EVs induce a metabolic reprogramming of fibroblasts by transferring miR-210 and miR-255 [63]. Since PKM2 and miR-210 are upregulated in melanoma hEVs, transfer of hEVs could cause a reprogramming towards a glycolytic metabolism of the recipient cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Walbrecq

Lecha

Gaigneaux

et al. 2020

Cancers

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Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to therapy, all favouring cancer progression. Small extracellular vesicles (EV) shuttle various cargos (proteins, miRNAs, DNA and others). Tumour-derived EVs can be taken up by neighbouring or distant cells in the tumour microenvironment, thus facilitating intercellular communication. The quantity of extracellular vesicle secretion and their composition can vary with changing microenvironmental conditions and disease states. Here, we investigated in melanoma cells the influence of hypoxia on the content and number of secreted EVs. Whole miRNome and proteome profiling revealed distinct expression patterns in normoxic or hypoxic growth conditions. Apart from the well-known miR-210, we identified miR-1290 as a novel hypoxia-associated microRNA, which was highly abundant in hypoxic EVs. On the other hand, miR-23a-5p and -23b-5p were consistently downregulated in hypoxic conditions, while the protein levels of the miR-23a/b-5p-predicted target IPO11 were concomitantly upregulated. Furthermore, hypoxic melanoma EVs exhibit a signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS), which were significantly associated with a poor prognosis for melanoma patients, indicating that proteins and/or miRNAs secreted by cancer cells may be exploited as biomarkers.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Walbrecq

Lecha

Gaigneaux

et al. 2020

Cancers

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“…In patient samples derived from metastatic melanomas, miR-210 expression was significantly elevated compared to nonmetastatic tumors [233]. Exosomes containing miR-210 are secreted by melanoma cells and can be taken up by surrounding fibroblasts [234]. This causes an increase in aerobic glycolysis and a decrease in oxidative phosphorylation in the fibroblasts, where miR-210 plays a pivotal role [234].…”

Section: Microrna-210mentioning

confidence: 99%

“…Exosomes containing miR-210 are secreted by melanoma cells and can be taken up by surrounding fibroblasts [234]. This causes an increase in aerobic glycolysis and a decrease in oxidative phosphorylation in the fibroblasts, where miR-210 plays a pivotal role [234]. The metabolic reprogramming of tumor surrounding fibroblasts increases extracellular acidification and may build a pro-metastatic environment [234][235][236].…”

Section: Microrna-210mentioning

confidence: 99%

“…This causes an increase in aerobic glycolysis and a decrease in oxidative phosphorylation in the fibroblasts, where miR-210 plays a pivotal role [234]. The metabolic reprogramming of tumor surrounding fibroblasts increases extracellular acidification and may build a pro-metastatic environment [234][235][236]. The small molecule methyl sulfone, has been shown to normalize the pro-metastatic metabolism of hypoxic melanoma cells via downregulating the expression of HIF-1α and, amongst others, simultaneously also reducing miR-210 expression [237].…”

Section: Microrna-210mentioning

confidence: 99%

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Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Linck-Paulus

Hellerbrand

Bosserhoff

et al. 2020

Cells

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In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

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“…In order to increase their glucose uptake, tumor cells can secrete and transfer miR-122-contaning exosomes to stromal cells, causing the reduction of the expression of pyruvate kinase M2 (PKM2) and glucose transporter 1 (GLUT1) in these cells, consequently increasing the glucose availability for cancer cells [121]. Additionally, human melanoma derived-exosomes contain miR-155 and miR-210 and deliver them to stromal cells, inducing a switch from OXPHOS to glycolysis (reverse Warburg effect), increasing extracellular acidification [122], which is considered to be among the causes of tumorigenesis [123].…”

Section: Extracellular Matrix Remodeling Via Mirna-containing Evsmentioning

confidence: 99%

Cancer-Derived Extracellular Vesicle-Associated MicroRNAs in Intercellular Communication: One Cell’s Trash Is Another Cell’s Treasure

Mills

Capece

Cocucci

et al. 2019

IJMS

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Several non-protein-coding genomic regions, previously marked as “junk DNA”, have been reported to be transcriptionally active, giving rise to non-coding RNA species implicated in fundamental biological and pathological processes. In particular, microRNAs (miRNAs), a class of small non-coding RNAs mediating post-transcriptional gene silencing, are causally involved in several human diseases, including various cancer types. Extracellular vesicles (EVs) are membranous structures physiologically released by most cell types. Initially, they were considered a “waste-removal” mechanism, through which cells could dispose unnecessary material and organelles. It is now widely demonstrated that EVs also play a critical role in intercellular communication, mediating the horizontal transfer of lipids, proteins, and genetic material. A paradigm shift in the biology of miRNAs was represented by the discovery that EVs, especially from cancer cells, contain miRs. EV-associated miRs act as autocrine, paracrine and endocrine factors, participating in cancer pathogenesis by modulating intercellular communication. Noteworthy, these formerly neglected molecules are now considered the next generation of cancer “theranostic” tools, with strong clinical relevance. In this review, we aim to summarize the most recent findings regarding EV-associated miRs in cancer pathogenesis and in the development of novel anti-neoplastic diagnostic and therapeutic approaches.

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Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment

Cited by 139 publications

References 63 publications

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cancer-Derived Extracellular Vesicle-Associated MicroRNAs in Intercellular Communication: One Cell’s Trash Is Another Cell’s Treasure

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