bims-exocan 2024-02-04 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2024‒02‒04
seventeen papers selected by
Muhammad Rizwan, COMSATS University

Exosomal circRHCG promotes breast cancer metastasis via facilitating M2 polarization through TFEB ubiquitination and degradation.
Roles of exosomes in immunotherapy for solid cancers.
Utilizing exosomes as sparking clinical biomarkers and therapeutic response in acute myeloid leukemia.
Recent Progress in the Application of Exosome Analysis in Ovarian Cancer Management.
Exosomal miR-361-3p promotes the viability of breast cancer cells by targeting ETV7 and BATF2 to upregulate the PAI-1/ERK pathway.
Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application.
Exosomal microRNAs in regulation of tumor cells resistance to apoptosis.
Exosomes containing miR-1469 regulate natural killer cells by targeting CD122 in non-segmental vitiligo.
[Intraperitoneal Transfer of miR-29b Containing Exosome Suppresses the Development of Peritoneal Metastases from Gastric Cancer].
Exosome-mediated circGMPS facilitates the development of gastric cancer cells through miR-144-3p/PUM1.
Engineered Exosomes Carrying miR-588 for Treatment of Triple Negative Breast Cancer Through Remodeling the Immunosuppressive Microenvironment.
A novel exosome based therapeutic intervention against neuroendocrine prostate cancer.
Decoding the regulatory landscape of lncRNAs as potential diagnostic and prognostic biomarkers for gastric and colorectal cancers.
Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells.
Navigating the brain: the role of exosomal shuttles in precision therapeutics.
Extracellular vesicle-derived non-coding RNAs in remodeling melanoma.
Mesenchymal stem cell-derived exosomes: Shaping the next era of stroke treatment.

NPJ Precis Oncol. 2024 Jan 29. 8(1): 22

Exosomal circRHCG promotes breast cancer metastasis via facilitating M2 polarization through TFEB ubiquitination and degradation.

Hong-Yu Shen, Jia-Lin Xu, Wei Zhang, Qin-Nan Chen, Zhen Zhu, Yuan Mao.

Triple-negative breast cancer (TNBC) is a highly aggressive cancer with distant metastasis. Accumulated evidence has demonstrated that exosomes are involved in TNBC metastasis. Elucidating the mechanism underlying TNBC metastasis has important clinical significance. In the present study, exosomes were isolated from clinical specimens and TNBC cell lines. Colony formation, EdU incorporation, wound healing, and transwell assays were performed to examine TNBC cell proliferation, migration, and metastasis. Macrophage polarization was evaluated by flow cytometry and RT-qPCR analysis of polarization markers. A mouse model of subcutaneous tumor was established for assessment of tumor growth and metastasis. RNA pull-down, RIP and Co-IP assays were used for analyzing molecular interactions. Here, we proved that high abundance of circRHCG was observed in exosomes derived from TNBC patients, and increased exosomal circRHCG indicated poor prognosis. Silencing of circRHCG suppressed TNBC cell proliferation, migration, and metastasis. TNBC cell-derived exosomes promoted M2 polarization via delivering circRHCG. Exosomal circRHCG stabilized BTRC mRNA via binding FUS and naturally enhanced BTRC expression, thus promoting the ubiquitination and degradation of TFEB in THP-1 cells. In addition, knockdown of BTRC or overexpression of TFEB counteracted exosomal circRHCG-mediated facilitation of M2 polarization. Furthermore, exosomal circRHCG promoted TNBC cell proliferation and metastasis by facilitating M2 polarization. Knockdown of circRHCG reduced tumor growth, metastasis, and M2 polarization through the BTRC/TFEB axis in vivo. In summary, exosomal circRHCG promotes M2 polarization by stabilizing BTRC and promoting TFEB degradation, thereby accelerating TNBC metastasis and growth. Our study provides promising therapeutic strategies against TNBC.

DOI: https://doi.org/10.1038/s41698-024-00507-y
Cell Death Dis. 2024 Feb 01. 15(2): 106

Roles of exosomes in immunotherapy for solid cancers.

Cong Lyu, Haifeng Sun, Zhenqiang Sun, Yang Liu, Qiming Wang.

Although immunotherapy has made breakthrough progress, its efficacy in solid tumours remains unsatisfactory. Exosomes are the main type of extracellular vesicles that can deliver various intracellular molecules to adjacent or distant cells and organs, mediating various biological functions. Studies have found that exosomes can both activate the immune system and inhibit the immune system. The antigen and major histocompatibility complex (MHC) carried in exosomes make it possible to develop them as anticancer vaccines. Exosomes derived from blood, urine, saliva and cerebrospinal fluid can be used as ideal biomarkers in cancer diagnosis and prognosis. In recent years, exosome-based therapy has made great progress in the fields of drug transportation and immunotherapy. Here, we review the composition and sources of exosomes in the solid cancer immune microenvironment and further elaborate on the potential mechanisms and pathways by which exosomes influence immunotherapy for solid cancers. Moreover, we summarize the potential clinical application prospects of engineered exosomes and exosome vaccines in immunotherapy for solid cancers. Eventually, these findings may open up avenues for determining the potential of exosomes for diagnosis, treatment, and prognosis in solid cancer immunotherapy.

DOI: https://doi.org/10.1038/s41419-024-06494-z
Front Immunol. 2023 ;14 1315453

Utilizing exosomes as sparking clinical biomarkers and therapeutic response in acute myeloid leukemia.

Wandi Wang, Xiaofang Wu, Jiamian Zheng, Ran Yin, Yangqiu Li, Xiuli Wu, Ling Xu, Zhenyi Jin.

  Acute myeloid leukemia (AML) is a malignant clonal tumor originating from immature myeloid hematopoietic cells in the bone marrow with rapid progression and poor prognosis. Therefore, an in-depth exploration of the pathogenesis of AML can provide new ideas for the treatment of AML. In recent years, it has been found that exosomes play an important role in the pathogenesis of AML. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention, which are key mediators of intercellular communication. Extracellular vesicles not only affect AML cells and normal hematopoietic cells but also have an impact on the bone marrow microenvironment and immune escape, thereby promoting the progression of AML and leading to refractory relapse. It is worth noting that exosomes and the various molecules they contain are expected to become the new markers for disease monitoring and prognosis of AML, and may also function as drug carriers and vaccines to enhance the treatment of leukemia. In this review, we mainly summarize to reveal the role of exosomes in AML pathogenesis, which helps us elucidate the application of exosomes in AML diagnosis and treatment.

Keywords:  acute myeloid leukemia; biomarker; exosomes; immune evasion; prognosis

DOI:  https://doi.org/10.3389/fimmu.2023.1315453
Curr Cancer Drug Targets. 2024 Jan 25.

Recent Progress in the Application of Exosome Analysis in Ovarian Cancer Management.

Vahideh Keyvani, Zari Naderi Ghale-Noie, Samaneh Mollazadeh, Reihaneh Alsadat Mahmoudian, Elnaz Ghorbani, Hamid Naderi, Majid Khazaei, Seyed Mahdi Hassanian, Gordon A Ferns, Amir Avan, Kazem Anvari.

  Exosomes are very small (nano-sized) vesicles participating in tumor development by involvement in intercellular communication mediated by transferring biocomponents. Exosomes appear to play vital roles in various cancer development, such as ovarian cancer, a common malignancy in women. Several hallmarks of ovarian cancer are reported to be affected by the exosome-- mediated cellular cross-talk, including modulating peritoneal dissemination and chemoresistance. Since the expression of some biomolecules, such as miRNAs and mRNA, is changed in ovarian cancer, these exo-biomolecules can be applied as prognostic, diagnostic, and therapeutic biomarkers. Also, the selective loading of specific chemotherapeutic agents into exosomes highlights these biocarries as potential delivery devices. Exosomes could be artificially provided and engineered to better target the site of interest in ovarian cancer. In the present review, we summarize the notable achievement of exosome application in ovarian cancer management to gain applicable transitional insight against this cancer.

Keywords:  Ovarian cancer; bioactive molecules; biomarkers; delivery vehicles.; exosomes

DOI:  https://doi.org/10.2174/0115680096281906231213055422
J Transl Med. 2024 Jan 28. 22(1): 112

Exosomal miR-361-3p promotes the viability of breast cancer cells by targeting ETV7 and BATF2 to upregulate the PAI-1/ERK pathway.

Yao Li, Lei Fan, An Yan, Xiaotian Ren, Yanyang Zhao, Bin Hua.

  BACKGROUND: Malignant progression is the major cause of poor prognosis in breast cancer (BC) patients. Plasma exosomal miRNAs have been reported to be involved in tumor progression, but their roles in BC remain unclear.METHODS: We performed plasma exosomal miRNA sequencing on 45 individuals, including healthy controls and nonmetastatic and metastatic BC patients. We examined the correlation between miRNA expression in tumor tissues and plasma exosomes in BC patients by qRT‒PCR. The effects of exosomal miR-361-3p on BC cells were determined by CellTiter-Glo, migration and wound healing assays. The target genes of miR-361-3p and downstream pathways were explored by dual-luciferase reporter assay, RNA knockdown, rescue experiments, and western blotting. We utilized murine xenograft model to further assess the impact of plasma exosomal miR-361-3p on the malignant progression of BC.
RESULTS: We found that the expression level of plasma exosomal miR-361-3p gradually increased with malignant progression in BC patients, and the expression of miR-361-3p in plasma exosomes and BC tissues was positively correlated. Consistently, exosomal miR-361-3p enhanced the migration and proliferation of two BC cell lines, MDA-MB-231 and SK-BR-3. Furthermore, our data showed that miR-361-3p inhibited two novel target genes, ETV7 and BATF2, to activate the PAI-1/ERK pathway, leading to increased BC cell viability. Finally, the consistency of the in vivo experimental results supported that elevated plasma exosomal miR-361-3p promote the malignant progression of BC.
CONCLUSIONS: We found for the first time that plasma exosomal miR-361-3p was associated with malignant progression in BC patients. Mechanistically, exosomal miR-361-3p can enhance the migration and proliferation of BC cells by targeting the ETV7 and BATF2/PAI-1/ERK pathways. Our data suggest that plasma exosomal miR-361-3p has the potential to serve as a biomarker for predicting malignant progression in BC patients.

Keywords:  Breast cancer; Exosomal miR-361-3p; Malignant progression; Migration; Proliferation

DOI:  https://doi.org/10.1186/s12967-024-04914-4
J Nanobiotechnology. 2024 Jan 28. 22(1): 41

Exosome-based delivery strategies for tumor therapy: an update on modification, loading, and clinical application.

Qian Yang, Shisheng Li, Haibo Ou, Yuming Zhang, Gangcai Zhu, Shaohong Li, Lanjie Lei.

  Malignancy is a major public health problem and among the leading lethal diseases worldwide. Although the current tumor treatment methods have therapeutic effect to a certain extent, they still have some shortcomings such as poor water solubility, short half-life, local and systemic toxicity. Therefore, how to deliver therapeutic agent so as to realize safe and effective anti-tumor therapy become a problem urgently to be solved in this field. As a medium of information exchange and material transport between cells, exosomes are considered to be a promising drug delivery carrier due to their nano-size, good biocompatibility, natural targeting, and easy modification. In this review, we summarize recent advances in the isolation, identification, drug loading, and modification of exosomes as drug carriers for tumor therapy alongside their application in tumor therapy. Basic knowledge of exosomes, such as their biogenesis, sources, and characterization methods, is also introduced herein. In addition, challenges related to the use of exosomes as drug delivery vehicles are discussed, along with future trends. This review provides a scientific basis for the application of exosome delivery systems in oncological therapy.

Keywords:  Drug delivery; Exosome; Isolation; Surface functionalization; Tumor therapy

DOI:  https://doi.org/10.1186/s12951-024-02298-7
Biochem Biophys Rep. 2024 Mar;37 101644

Exosomal microRNAs in regulation of tumor cells resistance to apoptosis.

Mohammad Salehi, Mohammad Javad Kamali, Daniyal Arab, Naghme Safaeian, Zahra Ashuori, Moein Maddahi, Narges Latifi, Amir Moein Jahromi.

  Exosomes are a type of extracellular vesicle that contains bioactive molecules that can be secreted by most cells. Nevertheless, the content of these cells differs depending on the cell from which they originate. The exosome plays a crucial role in modulating intercellular communication by conveying molecular messages to neighboring or distant cells. Cancer-derived exosomes can transfer several types of molecules into the tumor microenvironment, including high levels of microRNA (miRNA). These miRNAs significantly affect cell proliferation, angiogenesis, apoptosis resistance, metastasis, and immune evasion. Increasing evidence indicates that exosomal miRNAs (exomiRs) are crucial to regulating cancer resistance to apoptosis. In cancer cells, exomiRs orchestrate communication channels between them and their surrounding microenvironment, modulating gene expression and controlling apoptosis signaling pathways. This review presents an outline of present-day knowledge of the mechanisms that affect target cells and drive cancer resistance to apoptosis. Also, our study looks at the regulatory role of exomiRs in mediating intercellular communication between tumor cells and surrounding microenvironmental cells, specifically stromal and immune cells, to evade therapy-induced apoptosis.

Keywords:  Apoptosis; Cancer; Drug resistance; Exosome; MicroRNA

DOI:  https://doi.org/10.1016/j.bbrep.2024.101644
J Dermatol Sci. 2023 Dec 24. pii: S0923-1811(23)00269-4. [Epub ahead of print]

Exosomes containing miR-1469 regulate natural killer cells by targeting CD122 in non-segmental vitiligo.

Yujia Wei, Ting Zhou, Ronghua Pan, Xiaoqi Nie, Zhong Liu, Zeqi Shi, Ying Zeng, Ri Zhang, Yunhua Deng, Dong Li.

  BACKGROUND: Plasma exosomal microRNAs (miRNAs) have been used as potential biomarkers for various diseases and have been investigated for their possible involvement in the pathogenesis of vitiligo. However, the miRNA expression profile of plasma exosomes in patients with non-segmental vitiligo (NSV) has not been determined yet.OBJECTIVE: To screen differentially expressed microRNAs in plasma exosomes derived from patients with NSV and explore their roles in the pathogenesis of NSV.
METHODS: High-throughput sequencing was performed to determine the expression profiles of exosomal miRNAs in NSV. The effect of upregulated miR-1469 in NSV circulating exosomes on natural killer (NK) cells was further investigated using various molecular biological techniques.
RESULTS: MiR-1469 was identified as a candidate biomarker whose expression was significantly increased in circulating exosomes of NSV patients. Circulating exosomes were internalized by NK cells and increased NK cell proliferation viability and IFN-γ secretion capacity delivering miR-1469. Further studies revealed that the upregulation of CD122, the predicted target of miR-1469, could partially reverse the effect of miR-1469 on natural killer cells.
CONCLUSION: Alterations in plasma exosomal cargo occur in NSV and appear to contribute to NK cell dysfunction. Exosomal miR-1469 may be a biomarker of disease activity and could be used as a therapeutic drug target against innate immunity in NSV patients. The present study provides new insights into the role of exosomal miRNAs in NSV and suggests a novel miR-1469-CD122-IFN-γ pathway of NK cell underlying pathogenesis of NSV.

Keywords:  Exosomes; MicroRNA; Natural killer cells; Non-segmental vitiligo

DOI:  https://doi.org/10.1016/j.jdermsci.2023.12.006
Gan To Kagaku Ryoho. 2023 Dec;50(13): 1435-1437

[Intraperitoneal Transfer of miR-29b Containing Exosome Suppresses the Development of Peritoneal Metastases from Gastric Cancer].

Yuki Kimura, Hideyuki Ohzawa, Yuki Kaneko, Hideyo Miyato, Kentaro Kurashina, Shin Saito, Hironori Yamaguchi, Yoshinori Hosoya, Naohiro Sata, Joji Kitayama.

Although miR-29b levels in peritoneal exosomes was markedly reduced in patients with peritoneal metastases(PM), their role has not been fully clarified. Bone marrow derived mesenchymal stem cells(BMSC)were transfected with miR-29b- integrating lentivirus and exosomes isolated from culture supernatants using ultracentrifugation. The effects of the exosomes on human peritoneal mesothelial cells(HPMC)were examined in vitro. The in vivo effect of murine BMSC-derived exosomes was examined with a syngeneic PM model. Culture of HPMC with TGF-β1 decreased expression of E-cadherin and calretinin with increased expression of vimentin, totally restored by adding miR-29b-rich exosomes. The exosomes inhibited proliferation and migration of HPMC, and inhibited adhesion of gastric cancer cells to HPMC. Intraperitoneal(IP)transfer of miR- 29b-rich exosomes every 3 days markedly reduced the number of PM of a murine gastric cancer cell, YTN16P, on the mesentery of C57/BL6 mice. IP administration of miR-29b-containing exosome suppresses the development of PM of gastric cancer.
Cytotechnology. 2024 Feb;76(1): 53-68

Exosome-mediated circGMPS facilitates the development of gastric cancer cells through miR-144-3p/PUM1.

Yuexin Zhang, Wenrui Xie, Wenhong Zheng, Xiaoying Qian, Chengwei Deng.

  In recent years, gastric cancer (GC) is still one of the major public health burdens in the world. It is reported that exosome circular RNA (circRNA) is involved in the GC progression. However, the function and potential mechanism of circGMPS in GC remains unclear and needs further exploration. In this study, we isolated and identified exosomes from serum by TEM, NTA analysis and Western blot. RNA expression was evaluated by qRT-PCR. Western blot was employed to examine protein expression. Cell proliferation was measured using CCK-8. Transwell assay was adopted to analyze cell migration and invasion. The relationship between genes was explored through bioinformatics analysis, dual-luciferase reporter gene assay and spearman correlation coefficient. We found that circGMPS was elevated in GC exosomes, tissues and cells. Poor prognosis of GC patients was related to high circGMPS expression. Both exosome co-culture with cells and insertion of circGMPS clearly promoted cell progression. Mechanically, circGMPS sponged miR-144-3p to regulate PUM1. Inhibition of PUM1 or miR-144-3p overexpression inhibited the malignant GC cell progression. Our data confirmed that exosome-derived circGMPS boosted malignant progression by miR-144-3p/PUM1 axis in GC cells, providing strong evidences for circGMPS as a clinical biomarker of GC treatment.Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-023-00597-9.

Keywords:  Exosomes; Gastric cancer; PUM1; circGMPS; miR-144-3p

DOI:  https://doi.org/10.1007/s10616-023-00597-9
Int J Nanomedicine. 2024 ;19 743-758

Engineered Exosomes Carrying miR-588 for Treatment of Triple Negative Breast Cancer Through Remodeling the Immunosuppressive Microenvironment.

Zhengjia Zhang, Xinyi Luo, Xiaoxia Xue, Mingshi Pang, Xiangpeng Wang, Liuchunyang Yu, Jinxiu Qian, Xiaoyu Li, Meng Tian, Aiping Lu, Cheng Lu, Yuanyan Liu.

  Background: The morbidity and mortality of triple-negative breast cancer (TNBC) are still high, causing a heavy medical burden. CCL5, as a chemokine, can be involved in altering the composition of the tumor microenvironment (TME) as well as the immunosuppressive degree, and has become a very promising target for the treatment of TNBC. Dysregulation of microRNAs (miRNAs) in tumor tissues is closely related to tumor progression, and its utilization can be used to achieve therapeutic purposes. Engineered exosomes can avoid the shortcomings of miRNAs and also enhance their targeting and anti-tumor effects through engineering. Therefore, we aimed to create a cRGD-modified exosome for targeted delivery of miR-588 and to investigate its effect in remodeling immunosuppressive TME by anchoring CCL5 in TNBC.Methods: In this study, we loaded miR-588 into exosomes using electroporation and modified it with cRGD using post insertion to obtain cRGD-Exos/miR-588. Transmission electron microscopy (TEM), nanoparticle tracking assay technique (NTA), Western Blots, qPCR, and flow cytometry were applied for its characterization. CCK-8, qPCR and enzyme-linked immunosorbent assay (ELISA), in vivo fluorescence imaging system, immunohistochemistry and H&E staining were used to explore the efficacy as well as the mechanism at the cellular level as well as in subcutaneous graft-tumor nude mouse model.
Results: The cRGD-Exos/miR-588 was successfully constructed and had strong TNBC tumor targeting in vitro and in vivo. Meanwhile, it has significant efficacy on TME components affected by CCL5 and the degree of immunosuppression, which can effectively control TNBC with good safety.
Conclusion: In this experiment, cRGD-Exos/miR-588 was prepared to remodel immunosuppressive TME by anchoring CCL5, which is affected by the vicious cycle of immune escape. Overall, cRGD-Exos/miR-588 explored the feasibility of targeting TME for the TNBC treatment, and provided a competitive delivery system for the engineered exosomes to deliver miRNAs for antitumor therapy drug.

Keywords:  CCL5; engineered exosome; miR-588; triple negative breast cancer; tumor environment

DOI:  https://doi.org/10.2147/IJN.S440619
Sci Rep. 2024 Feb 02. 14(1): 2816

A novel exosome based therapeutic intervention against neuroendocrine prostate cancer.

Sharanjot Saini, Amritha Sreekumar, Sandip Nathani, Diana M Asante, Matthew N Simmons.

Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of castration-resistant prostate cancer (CRPC) with poor survival rates. Current treatment options for NEPC are limited to highly toxic platinum drugs highlighting the urgent need for new therapies. This study aimed to develop a novel therapeutic approach using engineered exosomes against NEPC. Exosomes were modified to target CEACAM5, an NEPC surface antigen, by attaching CEACAM5 antibodies to HEK293T exosomes. These exosomes were loaded with drugs inhibiting EZH2 and the androgen receptor (AR) as recent research shows a persistent role of AR in NEPC wherein it plays a concerted role with EZH2 in driving neuronal gene programs. In vitro experiments with NEPC cell lines demonstrated that CEACAM5-targeted exosomes were specifically taken up by NEPC cells, leading to reduced cellular viability and decreased expression of neuronal markers. Further in vivo tests using a NEPC patient-derived xenograft model (LuCaP145.1) showed significant tumor regression in mice treated with engineered exosomes compared to control mice receiving IgG-labeled exosomes. These results suggest that CEACAM5-engineered exosomes hold promise as a targeted therapy for NEPC. Importantly, our exosome engineering strategy is versatile and can be adapted to target various surface antigens in prostate cancer and other diseases.

DOI: https://doi.org/10.1038/s41598-024-53269-9
Clin Exp Med. 2024 Jan 31. 24(1): 29

Decoding the regulatory landscape of lncRNAs as potential diagnostic and prognostic biomarkers for gastric and colorectal cancers.

Arefeh Zabeti Touchaei, Sogand Vahidi, Ali Akbar Samadani.

  Colorectal cancer (CRC) and gastric cancer (GC) are major contributors to cancer-related mortality worldwide. Despite advancements in understanding molecular mechanisms and improved drug treatments, the overall survival rate for patients remains unsatisfactory. Metastasis and drug resistance are major challenges contributing to the high mortality rate in both CRC and GC. Recent research has shed light on the role of long noncoding RNAs (lncRNAs) in the development and progression of these cancers. LncRNAs regulate gene expression through various mechanisms, including epigenetic modifications and interactions with microRNAs (miRNAs) and proteins. They can serve as miRNA precursors or pseudogenes, modulating gene expression at transcriptional and post-transcriptional levels. Additionally, circulating lncRNAs have emerged as non-invasive biomarkers for the diagnosis, prognosis, and prediction of drug therapy response in CRC and GC. This review explores the intricate relationship between lncRNAs and CRC/GC, encompassing their roles in cancer development, progression, and chemoresistance. Furthermore, it discusses the potential of lncRNAs as therapeutic targets in these malignancies. The interplay between lncRNAs, miRNAs, and tumor microenvironment is also highlighted, emphasizing their impact on the complexity of cancer biology. Understanding the regulatory landscape and molecular mechanisms governed by lncRNAs in CRC and GC is crucial for the development of effective diagnostic and prognostic biomarkers, as well as novel therapeutic strategies. This review provides a comprehensive overview of the current knowledge and paves the way for further exploration of lncRNAs as key players in the management of CRC and GC.

Keywords:  Colorectal cancer; Drug resistance; Gastric cancer; Long noncoding RNA (lncRNA); Therapeutic targets

DOI:  https://doi.org/10.1007/s10238-023-01260-5
Cell Death Dis. 2024 Jan 30. 15(1): 102

Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells.

Wei Chen, Wang Peng, Ronghua Wang, Shuya Bai, Mengdie Cao, Si Xiong, Yanling Li, Yilei Yang, Jingwen Liang, Luyao Liu, Hamza O Yazdani, Yuchong Zhao, Bin Cheng.

Early metastasis is the primary factor in the very poor prognosis of pancreatic ductal adenocarcinoma (PDAC), with liver metastasis being the most common form of distant metastasis in PDAC. To investigate the mechanism of PDAC liver metastasis, we found that PDAC cells can promote the formation of pre-metastatic niches (PMNs) through exosomes to facilitate liver metastasis in the early stage. In our study, hepatic stellate cells (HSCs) were treated with PDAC-derived exosomes (PDAC-exo), and the activation of HSCs was detected. A novel transfer RNA-derived fragment, the tRF-GluCTC-0005 was obtained by small RNA sequencing from serum exosomes of PDAC patients. Bioinformatics analysis and RNA pull-down assays revealed the interaction between WDR1 and tRF-GluCTC-0005. A KPC transgenic mouse model and an AAV-mediated sh-WDR1 mouse model were used to detect the mechanism of liver metastasis in vivo. Finally, the dual luciferase reporter assay, protein mutation truncation assay, Co-IP assay, and flow cytometry assay were used to explore the molecular mechanism in HSCs activation and PMNs formation. We found that the tRF-GluCTC-0005 in exosomes binds to the 3' untranslated region of the mRNA of the WDRl in HSCs and increases mRNA stability. The N-terminals of WDR1 bind to the YAP protein directly, inhibit YAP phosphorylation, and promote the expression of YAP transcription factors. The tRF-GluCTC-0005 in PDAC-exo significantly recruits myeloid-derived suppressor cells (MDSCs) in the liver, creating a PMNs immunosuppressive microenvironment and further advancing liver metastasis from PDAC. Our results suggest that the key of PDAC liver metastasis is the activation of HSCs through upregulation of WDR1 by tRF-GluCTC-0005 in exosomes, which mediates the infiltration of MDSCs to form PMNs.

DOI: https://doi.org/10.1038/s41419-024-06482-3
Front Neurol. 2023 ;14 1324216

Navigating the brain: the role of exosomal shuttles in precision therapeutics.

Shaheera Fatima, Ariba Qaiser, Saadia Andleeb, Asraf Hussain Hashmi, Sobia Manzoor.

  Brain diseases have become one of the leading roots of mortality and disability worldwide, contributing a significant part of the disease burden on healthcare systems. The blood-brain barrier (BBB) is a primary physical and biological obstacle that allows only small molecules to pass through it. Its selective permeability is a significant challenge in delivering therapeutics into the brain for treating brain dysfunction. It is estimated that only 2% of the new central nervous system (CNS) therapeutic compounds can cross the BBB and achieve their therapeutic targets. Scientists are exploring various approaches to develop effective cargo delivery vehicles to promote better therapeutics targeting the brain with minimal off-target side effects. Despite different synthetic carriers, one of the natural brain cargo delivery systems, "exosomes," are now employed to transport drugs through the BBB. Exosomes are naturally occurring small extracellular vesicles (EVs) with unique advantages as a therapeutic delivery system for treating brain disorders. They have beneficial innate aspects of biocompatibility, higher stability, ability to cross BBB, low cytotoxicity, low immunogenicity, homing potential, targeted delivery, and reducing off-site target effects. In this review, we will discuss the limitations of synthetic carriers and the utilization of naturally occurring exosomes as brain-targeted cargo delivery vehicles and highlight the methods for modifying exosome surfaces and drug loading into exosomes. We will also enlist neurodegenerative disorders targeted with genetically modified exosomes for their treatment.

Keywords:  BBB; central nervous system (CNS); drug delivery; exosomes; therapeutic targets

DOI:  https://doi.org/10.3389/fneur.2023.1324216
Biomed Pharmacother. 2024 Feb 01. pii: S0753-3322(24)00094-5. [Epub ahead of print]172 116213

Extracellular vesicle-derived non-coding RNAs in remodeling melanoma.

Yuanyuan Zhan, Zihui Yang, Hong Zeng, Jing Yu, Xue Chen, Yiping Wu.

  Melanoma is one of the most lethal cutaneous malignancies. Despite great advances in radiotherapy, chemotherapy, and immunotherapy, the survival rate and prognosis of patients with melanoma remain poor. The abundant and sophisticated reciprocal communication network between melanoma cells and non-tumor cells contributes to the high heterogeneity of the melanoma microenvironment and is intimately related to varying treatment responses and clinical courses. Extracellular vesicles (EVs) are membrane structures generated by nearly all cell types. EVs contain biologically active molecules, mainly comprising proteins, lipids, and RNAs, and undoubtedly play multifaceted roles in numerous diseases, represented by melanoma. Non-coding RNAs (ncRNAs) mainly encompass long non-coding RNAs, microRNAs, and circular RNAs and constitute the majority of the human transcriptome. Multiple ncRNAs encapsulated in EVs coordinate various pathophysiological processes in melanoma. This review summarizes the mechanisms by which EV-ncRNAs modulate biological behaviors and immunity, and their potential diagnostic and therapeutic applications in melanoma. Undoubtedly, further insight into EV-ncRNAs and their functions in melanoma will contribute to the clinical treatment of melanoma and the implementation of precision medicine.

Keywords:  Diagnosis; Extracellular vesicles; Immune regulation; Melanoma; Non-coding RNAs; Therapy

DOI:  https://doi.org/10.1016/j.biopha.2024.116213
Neuroprotection. 2023 Dec;1(2): 99-116

Mesenchymal stem cell-derived exosomes: Shaping the next era of stroke treatment.

Arshi Waseem, Saudamini, Rizwanul Haque, Miroslaw Janowski, Syed Shadab Raza.

  Exosome-based treatments are gaining traction as a viable approach to addressing the various issues faced by an ischemic stroke. These extracellular vesicles, mainly produced by Mesenchymal Stem Cells (MSCs), exhibit many properties with substantial therapeutic potential. Exosomes are particularly appealing for stroke therapy because of their low immunogenicity, effective cargo transport, and ability to cross the blood-brain barrier. Their diverse effects include neuroprotection, angiogenesis stimulation, inflammatory response modulation, and cell death pathway attenuation, synergistically promoting neuronal survival, tissue regeneration, and functional recovery. Exosomes also show potential as diagnostic indicators for early stroke identification and customized treatment options. Despite these promising qualities, current exosome-based therapeutics have some limitations. The heterogeneity of exosome release among cell types, difficulty in standardization and isolation techniques, and complications linked to dosage and targeted administration necessitates extensive investigation. It is critical to thoroughly understand exosomal processes and their complicated interactions within the cellular milieu. To improve the practicality and efficacy of exosome-based medicines, research efforts must focus on improving production processes, developing robust evaluation criteria, and developing large-scale isolation techniques. Altogether, exosomes' multifunctional properties offer a new route for transforming stroke treatment and significantly improving patient outcomes.

Keywords:  Exosomes; Inflammatory Stress; Ischemic Stroke; Mesenchymal Stem Cells; Oxidative Stress

DOI:  https://doi.org/10.1002/nep3.30