title: Visualization of immediate immune responses to pioneer metastatic cells in the lung.
abstract: Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed 'waves' of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer anti-metastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding.
authors.affiliation: Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Headley
authors.affiliation: Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA.|Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef, 91105AZ Amsterdam, The Netherlands.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Bins
authors.affiliation: Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Nip
authors.affiliation: Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Roberts
authors.affiliation: Departments of Medicine and Laboratory Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW512, California 94143-0511, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
authors.affiliation: Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gerard
authors.affiliation: Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Krummel
mesh_terms: D000818:Animals; D002196:Capillaries / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000166:cytology; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000473:pathology