نبذة مختصرة : 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 V600EBRAF-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 (IMCs) producing PDGFA, TGFβ and CC chemokines are recruited to the stroma of premalignant lung adenomas through CC chemokine receptor 1 (CCR1)-dependent mechanisms. Stromal IMCs promote proliferation and transcriptional alterations suggestive of epithelial-mesenchymal transition in isolated premalignant lung tumour cells ex vivo, and are required for 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 (NPC2). Studies on isolated cells ex vivo confirm that NPC2 is secreted from tumour cells and is taken up by IMCs wherein it suppresses secretion of the CCR1 ligand CC chemokine 6 (CCL6), at least in part by facilitating its lysosomal degradation. Together, these findings show that NPC2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for development of chemopreventive strategies in lung cancer. ; This work was funded by Cancer Research UK programme grants (Ref C1362/A6969 and C1362/A13083). C.P. was also funded by a Royal Society-Wolfson Research Merit Award. We are indebted to the Department of Biomedical Services and the Advanced Imaging Facilities and Protein Nucleic Acid Chemistry Laboratory within Core Biotechnology Services at Leicester. We are also extremely grateful to Peter Lobel for providing the Npc2 mutant mice and NPC2-Alexa488. ; Peer-reviewed ; Publisher Version
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