title: Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S.
abstract: Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sevenich
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2].
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bowman
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2].
authors.forename: Steven D
authors.initials: SD
authors.lastname: Mason
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Quail
authors.affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Rapaport
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Benelita T
authors.initials: BT
authors.lastname: Elie
authors.affiliation: Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA.
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Virobay Inc., 1360 Willow Road, Menlo Park, California 94025, USA.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Holsinger
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Metastasis Research Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
authors.affiliation: Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
authors.affiliation: 1] Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Metastasis Research Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000473:pathology; D001859:Bone Neoplasms / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D001932:Brain Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015891:Cystatins / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D009928:Organ Specificity; D011480:Protease Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D015843:Serpins / Q000378:metabolism; D062725:Tight Junction Proteins / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C116891:CST7 protein, human; D015891:Cystatins; D011480:Protease Inhibitors; C516148:SERPINA3 protein, human; D015843:Serpins; D062725:Tight Junction Proteins; D002403:Cathepsins; C028217:cathepsin S
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