| 1. |
- Hoshino, Ayuko, et al.
(författare)
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Tumour exosome integrins determine organotropic metastasis
- 2015
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 527:7578, s. 329-
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Tidskriftsartikel (refereegranskat)abstract
- Ever since Stephen Pagets 1889 hypothesis, metastatic organotropism has remained one of cancers greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver-and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha(6)beta(4) and alpha(6)beta(1) were associated with lung metastasis, while exosomal integrin alpha(v)beta(5) was linked to liver metastasis. Targeting the integrins alpha(6)beta(4) and alpha(v)beta(5) decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
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| 2. |
- Bojmar, Linda, 1983-, et al.
(författare)
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Extracellular vesicle and particle isolation from human and murine cell lines, tissues, and bodily fluids
- 2021
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Ingår i: STAR protocols. - : Cell Press. - 2666-1667. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- We developed a modified protocol, based on differential ultracentrifugation (dUC), to isolate extracellular vesicles and particles (specifically exomeres) (EVPs) from various human and murine sources, including cell lines, surgically resected tumors and adjacent tissues, and bodily fluids, such as blood, lymphatic fluid, and bile. The diversity of these samples requires robust and highly reproducible protocols and refined isolation technology, such as asymmetric-flow field-flow fractionation (AF4). Our isolation protocol allows for preparation of EVPs for various downstream applications, including proteomic profiling. For complete details on the use and execution of this protocol, please refer to Hoshino et al. (2020).
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| 3. |
- Bojmar, Linda, et al.
(författare)
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miR-18a is regulated between progressive compartments of cancers, and incorporated in exosomes with the potential of creating premetastatic niches and predict cancer outcome
- 2015
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ultimate cause of death for many cancer patients is the spread of the cancer via metastasis. Even so, there are still a lack of knowledge regarding the metastasis process. This study was performed to investigate the role of metastamirs in exosomes and their metastatic patterns. We used the well-established isogeneic murine cancer model of low metastatic 67NR cells, mimicking luminal/basal breast tumors, and highly metastatic 4T1 cells with characteristics of basal breast tumors. We studied the exosomal properties and pre-metastatic effects in this metastasis model and compared human materials and exosomes of several other tumor types. Our data clearly demonstrated that exosomes from the highly metastatic cells home to the metastatic organs of their parental cells whereas exosomes from cells with low metastatic potential mostly located to lymph nodes. The exosome protein cargos also resembled their parental cells and potentially affects their target organs, and cells, differently. Furthermore, the exosomes from the highly metastatic cells had a more pronounced effect on tumor growth and pre-metastatic changes than the low metastatic exosomes. The microRNA-18a, a predictor of metastasis, was present to a higher extent in metastatic exosomes as compared to low metastatic exosomes, and altered the tumor progressive properties. Our findings support the role of exomirs as important players in the metastatic process, the value as biomarkers and potential therapeutic targets.
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| 4. |
- Bojmar, Linda, et al.
(författare)
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Protocol for cross-platform characterization of human and murine extracellular vesicles and particles
- 2024
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Ingår i: STAR PROTOCOLS. - : ELSEVIER. - 2666-1667. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of isolated extracellular vesicles and particles (EVPs) is crucial for determining functions and biomarker potential. Here, we present a protocol to analyze size, number, morphology, and EVP protein cargo and to validate EVP proteins in both humans and mice. We describe steps for nanoparticle tracking analysis, transmission electron microscopy, single-EVP immunodetection, EVP proteomic mass spectrometry and bioinformatic analysis, and EVP protein validation by ExoELISA and western blot analysis. This allows for EVP cross -validation across different platforms.For complete details on the use and execution of this protocol, please refer to Hoshino et al.1
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| 5. |
- Hoshino, Ayuko, et al.
(författare)
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Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers
- 2020
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Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 182:4, s. 1044-
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Tidskriftsartikel (refereegranskat)abstract
- There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n =151) and plasma-derived (n =120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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| 6. |
- Jiang, Haiying, et al.
(författare)
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A Highly Crystalline Wide-Band-Gap Conjugated Polymer toward High-Performance As-Cast Nonfullerene Polymer Solar Cells
- 2017
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Ingår i: ACS Applied Materials and Interfaces. - : AMER CHEMICAL SOC. - 1944-8244 .- 1944-8252. ; 9:41, s. 36061-36069
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Tidskriftsartikel (refereegranskat)abstract
- A new wide-band-gap conjugated polymer PBODT was successfully synthesized that showed high crystallinity and was utilized as, the active material in nonfullerene bulk-heterojunction, polymer solar cells (PSCs). The photovoltaic devices based on the as-cast blend films of PBODT with ITIC and IDIC acceptors showed notable power conversion efficiencies (PCEs) of 7.06% and 9:09%, with high open-circuit voltages of 1.00 and 0.93 V that correspond to low energy losses of 0.59 and 0.69 eV, respectively. In the case of PBODT:ITIC, lower exciton quenching efficiency and monomolecular recombination are found for devices with small driving force. On the other hand, the relatively higher driving force and suppressed monomolecular recombination for PBODT:IDIC devices are identified to be the reason for their higher short-circuit current density (J(sc)) and higher PCEs. In addition, when processed with the nonchlorinated solvent 1,2,4-trimethylbenzene, a good, PCE of 8.19% was still, achieved for the IDIC-based device. Our work shows that such wide-band-gap polymers have great potential for the environmentally friendly fabrication of highly efficient PSCs.
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| 7. |
- Wang, Gang, et al.
(författare)
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Tumour extracellular vesicles and particles induce liver metabolic dysfunction
- 2023
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Ingår i: Nature. - : NATURE PORTFOLIO. - 0028-0836 .- 1476-4687. ; 618:7964, s. 374-382
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Tidskriftsartikel (refereegranskat)abstract
- Cancer alters the function of multiple organs beyond those targeted by metastasis(1,2). Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.
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| 8. |
- Wang, Qin, et al.
(författare)
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Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR
- 2023
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Ingår i: NATURE METABOLISM. - 2522-5812. ; 5, s. 607-625
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Tidskriftsartikel (refereegranskat)abstract
- The lifetime risk of kidney disease in people with diabetes is 10-30%, implicating genetic predisposition in the cause of diabetic kidney disease (DKD). Here we identify an expression quantitative trait loci (QTLs) in the cis-acting regulatory region of the xanthine dehydrogenase, or xanthine oxidoreductase (Xor), a binding site for C/EBP beta, to be associated with diabetes-induced podocyte loss in DKD in male mice. We examine mouse inbred strains that are susceptible (DBA/2J) and resistant (C57BL/6J) to DKD, as well as a panel of recombinant inbred BXD mice, to map QTLs. We also uncover promoter XOR orthologue variants in humans associated with high risk of DKD. We introduced the risk variant into the 5 '-regulatory region of XOR in DKD-resistant mice, which resulted in increased Xor activity associated with podocyte depletion, albuminuria, oxidative stress and damage restricted to the glomerular endothelium, which increase further with type 1 diabetes, high-fat diet and ageing. Therefore, differential regulation of Xor contributes to phenotypic consequences with diabetes and ageing. Wang et al. identify a promoter variant in xanthine oxidoreductase associated with diabetic kidney disease through increased podocyte depletion and glomerular injury.
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