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Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.

ABSTRACT: Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. Although immune checkpoint inhibitors have improved outcomes in a subset of NSCLC patients, these effects are usually not durable. Thus, a more complete understanding of how immune niches within the tumor microenvironment (TME) promote NSCLC progression will allow us to build upon these advances. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-seq profiles of TIMs from several LUSC metastatic models with IMs of non-tumor bearing controls. We identified Spon1, a secreted extracellular matrix glycoprotein, as upregulated in TIMs and that Spon1 expression in LUSC tumors corresponds with poor survival. Bioinformatic analyses of the Cancer Genome Atlas (TCGA) revealed that LUSC tumors with high SPON1 expression significantly enriched for collagen extracellular matrix (ECM) signatures. Unexpectedly, we observed SPON1+ TIMs mediate their effects directly through LRP8 (ApoER2) on NSCLC cells, which results in TGFβ1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrate that SPON1+ TIMs are sufficient to promote NSCLC metastases. Additionally, we find that Spon1 loss in the host, or Lrp8 loss in cancer cells, results in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirm the relevance of the SPON1/LRP8/TGFβ1 axis with collagen production and survival in NSCLC patients. Taken together, our study describes how SPON1+ TIMs promotes collagen remodeling and NSCLC metastases through an LRP8-TGFβ1 signaling axis in lung cancer cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE260524 | GEO | 2024/03/05

REPOSITORIES: GEO

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Project description:Non-small cell lung cancer (NSCLC) is a major cause of cancer-associated mortality worldwide, and bone metastasis is the most prevalent event observed in patients with advanced NSCLC. However, the pathogenesis of bone metastases has not been fully elucidated. In the present study, differentially expressed genes (DEGs) were identified by gene expression microarray analysis of NSCLC tissue samples with or without bone metastases. Subsequently, collagen family collagen 6A1 (COL6A1) was chosen as the target gene through Ingenuity Pathway Analysis and reverse transcription-quantitative (RT-q)PCR validation of the top eight DEGs. COL6A1 was overexpressed or knocked down, and the proliferation and invasion of NSCLC cells was assessed using Cell Counting Kit-8, colony formation and Transwell invasion assays. Additionally, the osteogenic capacity of HOB and hES-MP 002.5 cells was assessed using RT-qPCR, western blotting, Alizarin Red staining and alkaline phosphatase staining. A total of 364 DEGs were identified in NSCLC tissues with bone metastases compared with NSCLC tissues without bone metastases, including 140 upregulated genes and 224 downregulated genes. Gene Ontology analysis indicated that the upregulated and downregulated genes were primarily enriched in ‘cellular process’, ‘metabolic process’ and ‘biological regulation’. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the upregulated genes were primarily enriched in ‘cysteine and methionine metabolism’, ‘oxidative phosphorylation’ and the ‘ribosome’, while the downregulated genes were primarily enriched in ‘transcriptional mis-regulation in cancer’, ‘ribosome’ and ‘mitophagy in animals’. COL6A1 was highly expressed in NSCLC tissue samples with bone metastases. Functionally, COL6A1 overexpression induced the proliferation and invasion of HARA cells, and knockdown prevented the proliferation and invasion of HARA-B4 cells. Finally, it was demonstrated that HOB and hES-MP 002.5 cells exhibited osteogenic capacity, and overexpression of COL6A1 in HARA cells increased adhesion of these cells to the osteoblasts, whereas knockdown of COL6A1 in HARA-B4 cells reduced their adhesive ability. In conclusion, COL6A1 may serve as a potential diagnostic marker and therapeutic target for bone metastasis in NSCLC.

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Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.

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