title: Serpins promote cancer cell survival and vascular co-option in brain metastasis.
abstract: Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Valiente
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Chaft
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Metastasis Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 21205, USA. Electronic address: j-massague@ski.mskcc.org.
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000556:secondary; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000378:metabolism*; D010960:Plasminogen Activators / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D000097522:Neuroserpin
chemical_list: D053222:Fas Ligand Protein; D005341:Fibrinolysin; D039842:Neural Cell Adhesion Molecule L1; D009479:Neuropeptides; D017396:Plasminogen Activator Inhibitor 2; D010960:Plasminogen Activators; D015843:Serpins; D000097522:Neuroserpin