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

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

  • JCI Insight. 2024 May 8;9(9):e168792. doi: 10.1172/jci.insight.168792.
Kristina M Whately 1,  Nisitha Sengottuvel 1 2,  Lincy Edatt 1,  Sonal Srivastava 3,  Allison T Woods 1 4,  Yihsuan S Tsai 5,  Alessandro Porrello 1,  Matthew P Zimmerman 1 4,  Aaron C Chack 1 2,  Stuart R Jefferys 1,  Gabriella Yacovone 1,  Dae Joong Kim 6,  Andrew C Dudley 6 7,  Antonio L Amelio 3 8,  Chad V Pecot 1 9 10
Affiliations

Affiliations

  • 1 UNC Lineberger Comprehensive Cancer Center and.
  • 2 Department of Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 3 Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
  • 4 Department of Cell Biology and Physiology and.
  • 5 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 6 Department of Microbiology, Immunology, and Cancer Biology and.
  • 7 UVA Comprehensive Cancer Center, The University of Virginia, Charlottesville, Virginia, USA.
  • 8 Department of Head and Neck-Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
  • 9 Division of Oncology and.
  • 10 RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
PMID: 38716730 DOI: 10.1172/jci.insight.168792
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. 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 inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-β1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in Cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-β1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-β1 signaling axis.

Keywords

Collagens; Immunology; Lung cancer; Monocytes; Oncology.

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