Fibroblast-Derived STC-1 Modulates Tumor-Associated Macrophages and Lung Adenocarcinoma Development

• Published in: Cell reports (Cambridge) Vol. 31; no. 12; p. 107802
• Main Authors: Kamata, Tamihiro, So, Tsz Y., Ahmed, Qasim, Giblett, Susan, Patel, Bipin, Luo, Jinli, Reddel, Roger, Pritchard, Catrin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.06.2020; Cell Press
• Subjects: Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Animals; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Differentiation; Disease Models, Animal; Disease Progression; Extracellular Space - metabolism; Fibroblasts - metabolism; Glycoproteins - deficiency; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; lung adenocarcinoma; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Membrane Glycoproteins - metabolism; Mice, Inbred C57BL; Protein Binding; Proto-Oncogene Proteins p21(ras) - metabolism; Receptors, Scavenger - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; stanniocalcin-1; Transforming Growth Factor beta1 - metabolism; tumor microenvironment; tumor-associated fibroblasts; tumor-associated macrophages; Tumor-Associated Macrophages - metabolism; Tumor-Associated Macrophages - pathology; tumor microenvironment; tumor-associated fibroblasts; lung adenocarcinoma; stanniocalcin-1; tumor-associated macrophages
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107802

The tumor microenvironment (TME) consists of different cell types, including tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs). How these cells interact and contribute to lung carcinogenesis remains elusive. Using G12DKRAS- and V600EBRAF-driven mouse lung models, we identify the pleiotropic glycoprotein stanniocalcin-1 (STC1) as a regulator of TAM-TAF interactions. STC1 is secreted by TAFs and suppresses TAM differentiation, at least in part, by sequestering the binding of GRP94, an autocrine macrophage-differentiation-inducing factor, to its cognate scavenger receptors. The accumulation of mature TAMs in the Stc1-deficient lung leads to enhanced secretion of TGF-β1 and, thus, TAF accumulation in the TME. Consistent with the mouse data, in human lung adenocarcinoma, STC1 expression is restricted to myofibroblasts, and a significant increase of naive macrophages is detected in STC1-high compared with STC1-low cases. This work increases our understanding of lung adenocarcinoma development and suggests new approaches for therapeutic targeting of the TME. [Display omitted] •STC1 is expressed and secreted from TAFs•STC1 depletion results in an accumulation of mature TAMs and TAFs in mouse lung models•Fibroblast-derived STC1 binds to GRP94, preventing macrophage differentiation•STC1high human lung adenocarcinomas have increased unpolarized TAMs The tumor microenvironment contains heterogeneous cell types, but how these cells interact to regulate tumor progression is unknown. Kamata et al. identify the fibroblast-derived, secreted glycoprotein STC1 as a paracrine regulator of tumor-associated macrophage differentiation in lung adenocarcinoma.