title: The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours.
abstract: 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 (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 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 (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 the development of chemopreventive strategies in lung cancer.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK tk83@le.ac.uk cap8@le.ac.uk.
authors.forename: Tamihiro
authors.initials: T
authors.lastname: Kamata
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Giblett
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Bipin
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Falguni
authors.initials: F
authors.lastname: Patel
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Foster
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK tk83@le.ac.uk cap8@le.ac.uk.
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D007108:Immune Tolerance; D008175:Lung Neoplasms / Q000473:pathology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D010196:Pancreatic Elastase / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C497045:Npc2 protein, mouse; D033921:Vesicular Transport Proteins; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D010196:Pancreatic Elastase; C017130:cholesterol-binding protein
keywords: CCR1; NPC2; V600
  EBRAF; lung adenoma; tumour‐associated macrophage‐lineage cells