ITGB3-enriched extracellular vesicles mediate the formation of osteoclastic pre-metastatic niche to promote lung adenocarcinoma bone metastasis
Rong Qiu
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Search for more papers by this authorYan Deng
College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
Search for more papers by this authorYue Lu
College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
Search for more papers by this authorXingyu Liu
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Search for more papers by this authorQin Huang
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Search for more papers by this authorCorresponding Author
Yuzhen Du
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Correspondence Yuzhen Du, Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233 China.
Email: [email protected]
Search for more papers by this authorRong Qiu
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Search for more papers by this authorYan Deng
College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
Search for more papers by this authorYue Lu
College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
Search for more papers by this authorXingyu Liu
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Search for more papers by this authorQin Huang
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Search for more papers by this authorCorresponding Author
Yuzhen Du
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Correspondence Yuzhen Du, Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233 China.
Email: [email protected]
Search for more papers by this authorRong Qiu and Yan Deng contributed equally to this work.
Abstract
The regulatory mechanisms underlying bone metastasis in lung adenocarcinoma (LUAD) are not yet fully understood despite the frequent occurrence of bone involvement. This study aimed to examine the involvement and mechanism of integrin subunit beta 3 (ITGB3) in the process of LUAD bone metastasis. Our findings indicate that ITGB3 facilitates the migration and invasion of LUAD cells in vitro and metastasis to the bone in vivo. Furthermore, ITGB3 stimulates osteoclast production and activation, thereby expediting osteolytic lesion progression. Extracellular vesicles (EVs) isolated from the conditioned medium (CM) of LUAD cells overexpressing ITGB3 determined that ITGB3 facilitates osteoclastogenesis and enhances osteoclast activity by utilizing EVs-mediated transport to RAW264.7 cells. Our in vivo findings demonstrated that ITGB3-EVs augmented the population of osteoclasts, thereby establishing an osteoclastic pre-metastatic niche (PMN) conducive to the colonization and subsequent growth of LUAD cells in the bone. ITGB3 is enriched in serum EVs of patients diagnosed with LUAD bone metastasis, potentially facilitating osteoclast differentiation and activation in vitro. Our research illustrates that ITGB3-EVs derived from LUAD cells facilitate osteoclast differentiation and activation by modulating the phosphorylation level of p38 MAPK. This process ultimately leads to the generation of osteolytic PMN and accelerates the progression of bone metastasis.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The datasets utilized and examined in the present study can be obtained from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| mc23803-sup-0001-sf1_tif.tif10.9 MB | Supporting information. |
| mc23803-sup-0002-sf2_tif.tif12.9 MB | Supporting information. |
| mc23803-sup-0003-sf3_tif.tif9 MB | Supporting information. |
| mc23803-sup-0004-sf4.tif3.5 MB | Supporting information. |
| mc23803-sup-0005-Supplementary_figure_legends.doc34.5 KB | Supporting information. |
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