CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved..
Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
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| Enthalten in: |
Cancer letters - 588(2024) vom: 28. Apr., Seite 216747 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Jiahui [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.04.2024 Date Revised 09.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.canlet.2024.216747 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM368930831 |
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Breast cancer | |
| 650 | 4 | |a CDK4/6 inhibitor resistance | |
| 650 | 4 | |a Cancer-associated fibroblasts | |
| 650 | 4 | |a Exosomes | |
| 650 | 4 | |a miR-20 | |
| 650 | 7 | |a Cyclin-Dependent Kinase 4 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Cyclin-Dependent Kinase 6 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
| 650 | 7 | |a CDK4 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
| 650 | 7 | |a CD63 protein, human |2 NLM | |
| 650 | 7 | |a Tetraspanin 30 |2 NLM | |
| 700 | 1 | |a Du, Ruoxin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaoju |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chenlin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Donghui |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xiangmei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guodong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Kuo |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shuning |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yingqi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cun |e verfasserin |4 aut | |
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