Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis

López, Ana Amor; Mazariegos, Marina S.; Capuano, Alessandra; Ximénez-Embún, Pilar; Hergueta-Redondo, Marta; Recio, Juan A.; Muñoz, Eva; Al‐Shahrour, Fátima; Muñoz, Javier; Megı́as, Diego; Doliana, Roberto; Spessotto, Paola; Peinado, Héctor

doi:10.3390/ijms22147406

Cited by 14 publications

(7 citation statements)

References 52 publications

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“…One limitation of our study is that due to the complete absence of nodal metastases in the FVB MMTV-Δ16HER2 mouse model, we could not assess the impact of EMILIN1 loss on the maintenance of lymphatic homeostasis and the regulation of lymph nodal spreading, as previously observed in other cancer types 14 , 28 , 40 . Nonetheless, our study of human breast cancer samples revealed a significant decrease in EMILIN1 expression in metastatic lesions, most of which were collected from lymph nodal locations.…”

Section: Discussionmentioning

confidence: 96%

Loss of the extracellular matrix glycoprotein EMILIN1 accelerates Δ16HER2-driven breast cancer initiation in mice

Favero,

Segatto,

Capuano

et al. 2024

npj Breast Cancer

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The extracellular matrix (ECM) is an important component of the tumor microenvironment and undergoes extensive remodeling during both initiation and progression of breast cancer (BC). EMILIN1 is an ECM glycoprotein, whose function has been linked to cancer and metastasis. However, EMILIN1 role during mammary gland and BC development has never been investigated. In silico and molecular analyses of human samples from normal mammary gland and BC showed that EMILIN1 expression was lower in tumors than in healthy mammary tissue and it predicted poor prognosis, particularly in HER2-positive BC. HER2+ BC accounts for 15-20% of all invasive BC and is characterized by high aggressiveness and poor prognosis. The Δ16HER2 isoform, a splice variant with very high oncogenic potential, is frequently expressed in HER2+ BC and correlates with metastatic disease. To elucidate the role of EMILIN1 in BC, we analyzed the phenotype of MMTV-Δ16HER2 transgenic mice, developing spontaneous multifocal mammary adenocarcinomas, crossed with EMILIN1 knock-out (KO) animals. We observed that Δ16HER2/EMILIN1 KO female mice exhibited an accelerated normal mammary gland development and a significantly anticipated appearance of palpable tumors (13.32 vs 15.28 weeks). This accelerated tumor initiation was corroborated by an increased number of tumor foci observed in mammary glands from Δ16HER2/EMILIN1 KO mice compared to the wild-type counterpart. Altogether our results underscore the centrality of ECM in the process of BC initiation and point to a role for EMILIN1 during normal mammary gland development and in protecting from HER2-driven breast tumorigenesis.

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Section: Discussionmentioning

confidence: 96%

Loss of the extracellular matrix glycoprotein EMILIN1 accelerates Δ16HER2-driven breast cancer initiation in mice

Favero,

Segatto,

Capuano

et al. 2024

npj Breast Cancer

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“…EMILIN1 produced by vascular smooth muscle cells is a major regulator of resting blood pressure levels (Litteri et al., 2012 ). Interestingly, EMILIN1 is proteolyzed and secreted in small EVs as a mechanism to reduce its intracellular level (Amor López et al., 2021 ). Smooth muscle cells in the vasculature undergo a number of changes in response to acute exercise (Newcomer et al., 2011 ), secrete EVs in vitro and in vivo (Kapustin & Shanahan, 2016 ), and are responsive to EV signalling from vascular endothelial cells in vitro (Boyer et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise

Giloteaux,

Glass,

Germain

et al. 2024

J of Extracellular Vesicle

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In healthy individuals, physical exercise improves cardiovascular health and muscle strength, alleviates fatigue and reduces the risk of chronic diseases. Although exercise is suggested as a lifestyle intervention to manage various chronic illnesses, it negatively affects people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), who suffer from exercise intolerance. We hypothesized that altered extracellular vesicle (EV) signalling in ME/CFS patients after an exercise challenge may contribute to their prolonged and exacerbated negative response to exertion (post‐exertional malaise). EVs were isolated by size exclusion chromatography from the plasma of 18 female ME/CFS patients and 17 age‐ and BMI‐matched female sedentary controls at three time points: before, 15 min, and 24 h after a maximal cardiopulmonary exercise test. EVs were characterized using nanoparticle tracking analysis and their protein cargo was quantified using Tandem Mass Tag‐based (TMT) proteomics. The results show that exercise affects the EV proteome in ME/CFS patients differently than in healthy individuals and that changes in EV proteins after exercise are strongly correlated with symptom severity in ME/CFS. Differentially abundant proteins in ME/CFS patients versus controls were involved in many pathways and systems, including coagulation processes, muscle contraction (both smooth and skeletal muscle), cytoskeletal proteins, the immune system and brain signalling.

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“…A study showed that the EMILIN family can induce tumor cell apoptosis by mimicking classical extracellular apoptosis pathways, and may be involved in regulating tumor angiogenesis by interacting with other extracellular matrix components or cell surface molecules ( 51 ). A Gene expression study in human NSCLC revealed that increased expression of EMILIN1 was associated with low proliferation of tumor cells ( 52 ). S100A8 belongs to the S100 protein family which is closely related to the regulation of intracellular Ca 2+ , cell proliferation, differentiation, movement, and apoptosis, and other cell functions ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer

Bao¹,

Huang²,

Lang³

et al. 2022

Transl Lung Cancer Res

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Background: Currently, the prognosis of patients with non-small cell lung cancer (NSCLC) remains unsatisfactory. This current study evaluated the relationship between histology of NSCLC and protein expression of exosomes in the plasma from NSCLC patients, and furthermore investigate the impact of the exosome profile on the tumor, node, metastasis (TNM) classification.Methods: Plasma samples were collected from 26 NSCLC patients before surgery. The exosomes were extracted from the plasma and liquid chromatography-mass spectrometry (LC/MS) was used to evaluate the expression of the proteins in the exosomes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the Cytoscape 3.8.2 software. Multivariate logistic regression and receiver operating characteristic (ROC) curves were used to identify proteins which could effectively distinguish between lung adenocarcinoma and lung squamous cell carcinoma. The relationship between protein expression and the TNM stage was calculated using Spearman rank correlation. Results:The expression levels of ZSWIM9, FYB1, SERPINF1, C1orf68, MASP2, and IGHV3-72 were higher in patients with lung adenocarcinoma compared to patients with lung squamous cell carcinoma.MFGE8 was associated with the occurrence of squamous cell carcinoma. CORO1A was positively correlated with the TNM stage of the patients, and COL4A2 was negatively correlated with TNM stage. GO and KEGG analyses revealed that cholesterol metabolism was important in NSCLC development.Conclusions: Lung adenocarcinoma may be distinguished from squamous cell carcinoma by the molecular profile of exosomes in the plasma samples. And, proteomics analysis suggested that cholesterol metabolism may play an important role of cancer progress in NSCLC.

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Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis

Cited by 14 publications

References 52 publications

Loss of the extracellular matrix glycoprotein EMILIN1 accelerates Δ16HER2-driven breast cancer initiation in mice

Loss of the extracellular matrix glycoprotein EMILIN1 accelerates Δ16HER2-driven breast cancer initiation in mice

Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise

Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer

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