Fibroblast-derived STC-1 modulates tumour associated macrophages and lung adenocarcinoma development

Abstract

The tumour microenvironment (TME) consists of different cell types including tumour-associated macrophages (TAMs) and tumour-associated fibroblasts (TAFs). How these cells interact and contribute to lung carcinogenesis remains elusive. Using G12DKRAS- and V600E BRAF-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 TGFb1 and thus TAF accumulation in the TME. Consistent with the mouse data, in human lung adenocarcinoma, STC1b expression is restricted to myofibroblasts and a significant increase of naïve macrophages is detected in STC1 -high compared to STC1 -low cases. This work increases our understanding of lung adenocarcinoma development and suggests new approaches for therapeutic targeting of the TME.</p