Extracellular vesicles from triple negative breast cancer promote pro-inflammatory macrophages associated with better clinical outcome

Tkach, Mercedes; Thalmensi, Jessie; Timperi, Eleonora; Gueguen, Paul; Névo, Nathalie; Grisard, Eleonora; Sirven, Philémon; Cocozza, Federico; Gouronnec, Alizée; Martín-Jaular, Lorena; San-Roman, Mabel Jouve; Delisle, Fabien; Manel, Nicolas; Rookhuizen, Derek C.; Guerin, Coralie L.; Soumelis, Vassili; Romano, Emanuela; Ségura, Elodie; Théry, Clotilde

doi:10.1073/pnas.2107394119

Cited by 59 publications

(57 citation statements)

References 72 publications

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“…As a good percentage of breast cancers in young women are of the TNBC subtype, it would be important to understand the nature of biomaterial packed within the circulating EVs from different subtypes of BCYW. In this context, the nature of the exosomal microRNA profile of TNBC BC patients has been shown to be different from those of HER2 positive patients in neoadjuvant treatment studies [ 77 ], and it has been shown that EVs from certain TNBC cases have the potential to modify the tumor immune microenvironment in favor of an improved prognosis [ 78 ]. Likewise, increased levels of microRNA-1246 and microRNA-155 in circulating exosomes from HER2-positive, transtuzumab-resistant breast cancer patients have been shown to be different from transtuzumab-resistant cases [ 79 ], raising the possibility of using the content of EVs in predicting the acquired therapeutic resistance.…”

Section: Discussionmentioning

confidence: 99%

Delineation of Pathogenomic Insights of Breast Cancer in Young Women

Paul

George

Saini

et al. 2022

Cells

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The prognosis of breast cancer (BC) in young women (BCYW) aged ≤40 years tends to be poorer than that in older patients due to aggressive phenotypes, late diagnosis, distinct biologic, and poorly understood genomic features of BCYW. Considering the estimated predisposition of only approximately 15% of the BC population to BC-promoting genes, the underlying reasons for an increased occurrence of BCYW, at large, cannot be completely explained based on general risk factors for BC. This underscores the need for the development of next-generation of tissue- and body fluid-based prognostic and predictive biomarkers for BCYW. Here, we identified the genes associated with BCYW with a particular focus on the age, intrinsic BC subtypes, matched normal or normal breast tissues, and BC laterality. In young women with BC, we observed dysregulation of age-associated cancer-relevant gene sets in both cancer and normal breast tissues, sub-sets of which substantially affected the overall survival (OS) or relapse-free survival (RFS) of patients with BC and exhibited statically significant correlations with several gene modules associated with cellular processes such as the stroma, immune responses, mitotic progression, early response, and steroid responses. For example, high expression of COL1A2, COL5A2, COL5A1, NPY1R, and KIAA1644 mRNAs in the BC and normal breast tissues from young women correlated with a substantial reduction in the OS and RFS of BC patients with increased levels of these exemplified genes. Many of the genes upregulated in BCYW were overexpressed or underexpressed in normal breast tissues, which might provide clues regarding the potential involvement of such genes in the development of BC later in life. Many of BCYW-associated gene products were also found in the extracellular microvesicles/exosomes secreted from breast and other cancer cell-types as well as in body fluids such as urine, saliva, breast milk, and plasma, raising the possibility of using such approaches in the development of non-invasive, predictive and prognostic biomarkers. In conclusion, the findings of this study delineated the pathogenomics of BCYW, providing clues for future exploration of the potential predictive and prognostic importance of candidate BCYW molecules and research strategies as well as a rationale to undertake a prospective clinical study to examine some of testable hypotheses presented here. In addition, the results presented here provide a framework to bring out the importance of geographical disparities, to overcome the current bottlenecks in BCYW, and to make the next quantum leap for sporadic BCYW research and treatment.

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Section: Discussionmentioning

confidence: 99%

Delineation of Pathogenomic Insights of Breast Cancer in Young Women

Paul

George

Saini

et al. 2022

Cells

View full text Add to dashboard Cite

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“…Apart from their physiological role as cellular mediators, the potential use of EVs as a nanoplatform for the development of advanced nanomedicine has gained ever-increasing attention in the scientific community thanks to the biocompatibility of these vesicles, as well as their natural cargo and their potential ability to induce several pathways’ activation/modification in recipient cells [ 108 , 109 ].…”

Section: Extracellular Vesicles From Cellular Communication Mediators...mentioning

confidence: 99%

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

et al. 2022

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The incidence of cancer is increasing dramatically, affecting all ages of the population and reaching an ever higher worldwide mortality rate. The lack of therapies’ efficacy is due to several factors such as a delay in diagnosis, tumor regrowth after surgical resection and the occurrence of multidrug resistance (MDR). Tumor-associated immune cells and the tumor microenvironment (TME) deeply affect the tumor’s progression, leading to several physicochemical changes compared to physiological conditions. In this scenario, macrophages play a crucial role, participating both in tumor suppression or progression based on the polarization of onco-suppressive M1 or pro-oncogenic M2 phenotypes. Moreover, much evidence supports the pivotal role of macrophage-derived extracellular vesicles (EVs) as mediators in TME, because of their ability to shuttle the cell–cell and organ–cell communications, by delivering nucleic acids and proteins. EVs are lipid-based nanosystems with a broad size range distribution, which reflect a similar composition of native parent cells, thus providing a natural selectivity towards target sites. In this review, we discuss the impact of macrophage-derived EVs in the cancer’s fate as well as their potential implications for the development of personalized anticancer nanomedicine.

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“…Intriguingly, we did not observe any substantial differences in the filaggrin-related cargo as far as the calcium level was concerned which is unexpected given the large increase in filaggrin expression upon NHEK differentiation. To improve the sensitivity of detection we next pooled fractions 1-5 (Figure 2d) adjusting the samples against cell counts (as in [26][27][28] ), which revealed the band of ~75 kDa in size (possibly filaggrin dimer, Figure 2d) to be the most prominent; the 37 kDa filaggrin monomer band could be also sometimes detected at lower levels in the vesicles harvested from differentiated NHEKs. Unexpectedly, the differences between sEV/exosomes obtained from the two calcium conditions were relatively small.…”

Section: Profilaggrin/filaggrin Segregate Into Small Evs Secreted By ...mentioning

confidence: 99%

Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2-dependent fashion

Hovhannisyan

Kobiela

Serna

et al. 2022

Preprint

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Filaggrin (FLG) protein is indispensable for multiple aspects of the epidermal barrier function but its accumulation in a monomeric filaggrin form may initiate premature keratinocytes death; it is unclear how filaggrin levels are controlled before the formation of storing keratohyalin granules. Here we show that keratinocyte-secreted small extracellular vesicles (sEVs) may contain filaggrin-related cargo providing a route of eliminating excess filaggrin from keratinocytes. Filaggrin-containing sEVs are found in plasma in both healthy individuals and atopic dermatitis patients. Staphylococcus aureus (S. aureus) enhances packaging and secretion of filaggrin-relevant products within the sEVs for enhanced export via a TLR2-mediated mechanism which is also linked to the ubiquitination process. This filaggrin removal system, preventing premature keratinocyte death and epidermal barrier dysfunction, is exploited by S. aureus which promotes filaggrin elimination from the skin that could help safeguard bacterial growth.

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Extracellular vesicles from triple negative breast cancer promote pro-inflammatory macrophages associated with better clinical outcome

Cited by 59 publications

References 72 publications

Delineation of Pathogenomic Insights of Breast Cancer in Young Women

Delineation of Pathogenomic Insights of Breast Cancer in Young Women

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2-dependent fashion

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