Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases
Copyright © 2022 Elsevier B.V. All rights reserved..
Mechanisms underlying breast cancer brain metastasis (BCBM) are still unclear. In this study, we observed that extracellular vesicles (EVs) secreted from breast cancer cells with increased expression of tGLI1, a BCBM-promoting transcription factor, strongly activated astrocytes. EV-derived microRNA/miRNA microarray revealed tGLI1-positive breast cancer cells highly secreted miR-1290 and miR-1246 encapsulated in EVs. Genetic knockin/knockout studies established a direct link between tGLI1 and both miRNAs. Datamining and analysis of patient samples revealed that BCBM patients had more circulating EV-miRs-1290/1246 than those without metastasis. Ectopic expression of miR-1290 or miR-1246 strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-1290- or miR-1246-overexpressing astrocytes promoted mammospheres. Furthermore, miRs-1290/1246 suppressed expression of FOXA2 transcription repressor, leading to CNTF cytokine secretion and subsequent activation of astrocytes. Finally, we conducted a mouse study to demonstrate that astrocytes overexpressing miR-1290, but not miR-1246, enhanced intracranial colonization and growth of breast cancer cells. Collectively, our findings demonstrate, for the first time, that breast cancer EV-derived miR-1290 and miR-1246 activate astrocytes in the brain metastatic microenvironment and that EV-derived miR-1290 promotes progression of brain metastases through the novel EV-miR-1290→FOXA2→CNTF signaling axis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:540 |
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| Enthalten in: |
Cancer letters - 540(2022) vom: 01. Aug., Seite 215726 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sirkisoon, Sherona R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.06.2022 Date Revised 02.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.canlet.2022.215726 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Sirkisoon, Sherona R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Revised 02.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
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| 520 | |a Copyright © 2022 Elsevier B.V. All rights reserved. | ||
| 520 | |a Mechanisms underlying breast cancer brain metastasis (BCBM) are still unclear. In this study, we observed that extracellular vesicles (EVs) secreted from breast cancer cells with increased expression of tGLI1, a BCBM-promoting transcription factor, strongly activated astrocytes. EV-derived microRNA/miRNA microarray revealed tGLI1-positive breast cancer cells highly secreted miR-1290 and miR-1246 encapsulated in EVs. Genetic knockin/knockout studies established a direct link between tGLI1 and both miRNAs. Datamining and analysis of patient samples revealed that BCBM patients had more circulating EV-miRs-1290/1246 than those without metastasis. Ectopic expression of miR-1290 or miR-1246 strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-1290- or miR-1246-overexpressing astrocytes promoted mammospheres. Furthermore, miRs-1290/1246 suppressed expression of FOXA2 transcription repressor, leading to CNTF cytokine secretion and subsequent activation of astrocytes. Finally, we conducted a mouse study to demonstrate that astrocytes overexpressing miR-1290, but not miR-1246, enhanced intracranial colonization and growth of breast cancer cells. Collectively, our findings demonstrate, for the first time, that breast cancer EV-derived miR-1290 and miR-1246 activate astrocytes in the brain metastatic microenvironment and that EV-derived miR-1290 promotes progression of brain metastases through the novel EV-miR-1290→FOXA2→CNTF signaling axis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Brain microenvironment | |
| 650 | 4 | |a Breast cancer brain metastasis | |
| 650 | 4 | |a Extracellular vesicles | |
| 650 | 4 | |a microRNAs | |
| 650 | 4 | |a tGLI1 | |
| 650 | 7 | |a Ciliary Neurotrophic Factor |2 NLM | |
| 650 | 7 | |a FOXA2 protein, human |2 NLM | |
| 650 | 7 | |a MIRN1290 microRNA, human |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Hepatocyte Nuclear Factor 3-beta |2 NLM | |
| 650 | 7 | |a 135845-92-0 |2 NLM | |
| 700 | 1 | |a Wong, Grace L |e verfasserin |4 aut | |
| 700 | 1 | |a Aguayo, Noah R |e verfasserin |4 aut | |
| 700 | 1 | |a Doheny, Daniel L |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Dongqin |e verfasserin |4 aut | |
| 700 | 1 | |a Regua, Angelina T |e verfasserin |4 aut | |
| 700 | 1 | |a Arrigo, Austin |e verfasserin |4 aut | |
| 700 | 1 | |a Manore, Sara G |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Calvin |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Ravi |e verfasserin |4 aut | |
| 700 | 1 | |a Xing, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Guangxu |e verfasserin |4 aut | |
| 700 | 1 | |a Watabe, Kounosuke |e verfasserin |4 aut | |
| 700 | 1 | |a Lo, Hui-Wen |e verfasserin |4 aut | |
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