The cholesterol‐binding protein NPC 2 restrains recruitment of stromal macrophage‐lineage cells to early‐stage lung tumours

The tumour microenvironment is known to play an integral role in facilitating cancer progression at advanced stages, but its function in some pre‐cancerous lesions remains elusive. We have used the V600 E BRAF ‐driven mouse lung model that develop premalignant lesions to understand stroma–tumour interactions during pre‐cancerous development. In this model, we have found that immature macrophage‐lineage cells ( IMC s) producing PDGFA , TGF β and CC chemokines are recruited to the stroma of premalignant lung adenomas through CC chemokine receptor 1 ( CCR 1)‐dependent mechanisms. Stromal IMC s promote proliferation and transcriptional alterations suggestive of epithelial–mesenchymal transition in isolated premalignant lung tumour cells ex vivo , and are required for the maintenance of early‐stage lung tumours in vivo . Furthermore, we have found that IMC recruitment to the microenvironment is restrained by the cholesterol‐binding protein, Niemann‐Pick type C2 ( NPC 2). Studies on isolated cells ex vivo confirm that NPC 2 is secreted from tumour cells and is taken up by IMC s wherein it suppresses secretion of the CCR 1 ligand CC chemokine 6 ( CCL 6), at least in part by facilitating its lysosomal degradation. Together, these findings show that NPC 2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for the development of chemopreventive strategies in lung cancer.