Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment

Xie, Zhibo; Gao, Ya; Ho, Chia-Kang; Li, Le‐Qun; Jin, Chen; Wang, Xiaoyi; Zou, Caifeng; Mao, Yishen; Wang, Xiaobo; Li, Qingfeng; Fu, Deliang; Zhang, Yifan

doi:10.1136/gutjnl-2020-323014

Cited by 114 publications

(92 citation statements)

References 45 publications

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“…As examples, extracellular vesicles-mediated delivery of ITIH4 to target cells regulated cell growth and inflammatory response 42 and extracellular vesicles-mediated delivery of TGF-β, Smad2, and Smad4 modulated neuroinflammation and protected against ischemic stroke. 49 Xie et al 50 also reported that extracellular vesicles-shuttled CD44v6/C1QBP complex can drive liver metastasis of pancreatic cancer. Thus, we next investigated the role of protein cargoes in mediating the beneficial effects of MEVs.…”

Section: Discussionmentioning

confidence: 98%

Extracellular vesicles derived from melatonin‐preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2

Liu

Tang

Wang

et al. 2021

Journal of Pineal Research

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Spinal cord injury (SCI) is a devastating trauma that leads to irreversible motor and sensory dysfunction and is, so far, without effective treatment. Recently, however, nano-sized extracellular vesicles derived from preconditioned mesenchymal stem cells (MSCs) have shown great promise in treating various diseases, including SCI. In this study, we investigated whether extracellular vesicles (MEVs) derived from MSCs pretreated with melatonin (MT), which is well recognized to be useful in treating diseases, including Alzheimer's disease, non-small cell lung cancer, acute ischemia-reperfusion liver injury, chronic kidney disease, and SCI, are better able to promote functional recovery in mice after SCI than extracellular vesicles derived from MSCs without preconditioning (EVs). MEVs were found to facilitate motor behavioral recovery more than EVs and to increase microglia/macrophages polarization from M1-like to M2like in mice. Experiments in BV2 microglia and RAW264.7 macrophages confirmed that MEVs facilitate M2-like polarization and also showed that they reduce the production of reactive oxygen species (ROS) and regulate mitochondrial function. Proteomics analysis revealed that ubiquitin-specific protease 29 (USP29) was markedly increased in MEVs, and knockdown of USP29 in MEVs (shUSP29-MEVs) abolished MEVs-mediated benefits in vitro and in vivo. We then showed that USP29 interacts with, deubiquitinates and therefore stabilizes nuclear factor-like 2 (NRF2), thereby regulating microglia/macrophages polarization. In NRF2 knockout mice, MEVs failed to promote functional recovery and M2-like microglia/macrophages polarization. We also showed that MT reduced global N6-methyladenosine (m 6 A) modification and levels of the m 6 A "writer" methyltransferase-like 3 (METTL3). The stability of USP29 mRNA in MSCs was enhanced by treatment with MT, but inhibited by overexpression of METTL3.This study describes a very promising extracellular vesicle-based approach for treating SCI.

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Section: Discussionmentioning

confidence: 98%

Extracellular vesicles derived from melatonin‐preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2

Liu

Tang

Wang

et al. 2021

Journal of Pineal Research

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“…Recently, Stefanius, K. et al report that exosomes from PDAC initiate cell transformation by stimulating NIH/3T3 recipient cells [90]. Xie, Z. et al found the exosome CD44v6/C1QBP derived from PDAC formulate the hepatic metastasis microenvironment [40]. As an important carrier, the functions of exosomes are realized through their contents, and miRNA is one of the most abundant cargo [91].…”

Section: Discussionmentioning

confidence: 99%

“…Exosomes can detected in varieties of body uids, including blood, urine, bile, ascites and so on [34,35], therefore, they can be used as the novel templates for tumor diagnostic [36][37][38]. Multiple functions of exosomes in PDAC have been reported [29,[39][40][41], we found that exosomes serve as a "bridge" between PDAC and CAFs, and CAFs are important component of the tumor microenvironment (TME).…”

Section: Introductionmentioning

confidence: 88%

Lnc-FSD2-31:1 in Pancreatic ductal adenocarcinoma promotes ATG7-mediated proliferation and fibrosis of cancer associated fibroblasts via exosome miR-4736

Geng

Luo

et al. 2022

Preprint

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Background Long non-coding RNA (lncRNA) is closely related to the occurrence of Pancreatic ductal adenocarcinoma (PDAC). Intercellular interactions between cancer associated fibroblasts (CAFs) and cancer cells influence malignant proliferation and chemotherapy resistance of PDAC in a variety of ways. We performed the global expression profiles of lncRNA between longevity and short survival PDAC patients’ pancreatic tissues, to identify molecular mechanism of PDAC. Method Tissue microarray (TMA) was used to explore survival related lncRNA in PDAC. The localization of lncRNA was conform by RNA fluorescence in-situ hybridization (FISH) analysis. Functional assays were introduced to demonstrate the anti-tumor effects of lncRNA in vitro and in vivo. Exosomes and primary CAFs were isolated from PDAC cell lines and patient tissues. Bioinformatics and 3D co-culture model were used to find the downstream targets. KPC transgenic mouse model and human cytokine array were also applied to detect the mechanism of PDAC. Results We found that lnc-FSD2-31:1 was elevated significantly in longevity survival patients. Lnc-FSD2-31:1 suppressed PDAC proliferation, invasion, and metastasis in vitro and in vivo. Lnc-FSD2-31:1 also act as a competing endogenous RNA (ceRNA) to inhibit miR-4736 expression in PDAC cells. Exosome miR-4736 secreted by PDAC was transported to CAFs. We found miR-4736 inhibited the proliferation, autophagy and promoted the fibrosis of CAFs by binding to the 3’-untranslated region(3’-UTR) of ATG7. Under the stimulatory of miR-4736, CAFs particularly secreted IL-32α, IL-1β, IL-1ra, G-CSF, IL-2, IL-4. Furthermore, miR-4736 antagomir intraperitoneally injected can suppressed tumor growth in KPC mice. Exosome miR-4736 of plasma might be a biomarker of PDAC. Conclusions Lnc-FSD2-31:1 suppress PDAC progression and act as a competing endogenous RNA (ceRNA) to inhibit miR-4736 expression in PDAC cells. Exosome miR-4736 released by PDAC inhibit autophagy and promote fibrosis of CAFs via targeting ATG7. miR-4736 might be a promising biomarker and treatment target of PDAC.

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“…Li et al reported that exosomal miRNA-19b-3p from tubular epithelial cells contributed to M1 macrophage activation in kidney damage [ 45 ]. A recent research showed that Pancreatic ductal adenocarcinoma derived exosome carried CD44v6/ C1QBP complex to promote pancreatic cancer liver metastasis [ 46 ]. Ju et al showed that grape exosome-like nanoparticles gradually accumulated in the gut 6 hours after administration [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Human Adipose Mesenchymal Stem Cell-derived Exosomes Protect Mice from DSS-Induced Inflammatory Bowel Disease by Promoting Intestinal-stem-cell and Epithelial Regeneration

Yu¹,

Yang²,

Xiao³

et al. 2021

Aging and disease

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Inflammatory bowel disease (IBD) remains a severe disease for most patients, with its incidence and prevalence increasingly globally. Currently, there is no effective treatments for IBD, and traditional treatments have multiple side effects. Therefore, novel therapeutic strategies or alternative drugs are urgently needed. Previous studies have shown that mesenchymal stem cell-derived exosomes have exhibited promising therapeutic effects on inflammatory disease. Here, we performed intravenous injection of human adipose mesenchymal stem cell (hADSC)-derived exosomes (hADSC-Exo) in a DSS-induced IBD mouse model and found that hADSC-Exo promoted functional recovery, downregulated inflammatory responses, reduced intestine cell apoptosis, increased epithelial regeneration and maintained intestinal barrier integrity. Moreover, we established a colon organoid, hADSC-Exo and TNF-α co-cultured system to explore the protective effect of hADSC-Exo on integrity of intestine mucosa and epithelial regeneration. We showed that hADSC-Exo not only can promote the proliferation and regeneration of Lgr5 + ISCs and epithelial cells but also ameliorate the inflammation damage in TNF-α induced inflammatory damaged mice colon organoids. Taken together, our findings indicate that hADSC-Exo protects intestine integrity, activates intestine epithelial cell and ISCs proliferation, suggesting that hADSC-Exo might be a potential effective treatment approach for IBD. We also provide a theoretical basis for new therapeutic strategies for cell-free therapy in inflammatory bowel disease.

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Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment

Cited by 114 publications

References 45 publications

Extracellular vesicles derived from melatonin‐preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2

Extracellular vesicles derived from melatonin‐preconditioned mesenchymal stem cells containing USP29 repair traumatic spinal cord injury by stabilizing NRF2

Lnc-FSD2-31:1 in Pancreatic ductal adenocarcinoma promotes ATG7-mediated proliferation and fibrosis of cancer associated fibroblasts via exosome miR-4736

Human Adipose Mesenchymal Stem Cell-derived Exosomes Protect Mice from DSS-Induced Inflammatory Bowel Disease by Promoting Intestinal-stem-cell and Epithelial Regeneration

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