Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S

• Published in: Nature cell biology Vol. 16; no. 9; pp. 876 - 888
• Main Authors: Sevenich, Lisa, Bowman, Robert L., Mason, Steven D., Quail, Daniela F., Rapaport, Franck, Elie, Benelita T., Brogi, Edi, Brastianos, Priscilla K., Hahn, William C., Holsinger, Leslie J., Massagué, Joan, Leslie, Christina S., Joyce, Johanna A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2014; Nature Publishing Group
• Subjects: 13/106; 13/2; 13/31; 13/51; 13/89; 45; 45/61; 59; 59/5; 631/67/322; 631/67/327; Adhesion; Animals; Antineoplastic Agents - pharmacology; Biology; Biomarkers, Tumor - metabolism; Blood-Brain Barrier - pathology; Bone Neoplasms - enzymology; Bone Neoplasms - mortality; Bone Neoplasms - secondary; Brain Neoplasms - enzymology; Brain Neoplasms - mortality; Brain Neoplasms - secondary; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cancer cells; Cancer Research; Cathepsins; Cathepsins - antagonists & inhibitors; Cathepsins - physiology; Cell Biology; Cell Line, Tumor; Cell Movement; Cells; Cystatins - metabolism; Development and progression; Developmental Biology; Disease-Free Survival; Female; Gene expression; Health aspects; Humans; Kaplan-Meier Estimate; Life Sciences; Lung Neoplasms - enzymology; Lung Neoplasms - mortality; Lung Neoplasms - secondary; Metastasis; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, Nude; Mice, SCID; Oncology; Organ Specificity; Physiological aspects; Protease Inhibitors - pharmacology; Proteolysis; Serpins - metabolism; Stem Cells; Tight Junction Proteins - metabolism; Tumor Microenvironment; Tumors; Xenograft Model Antitumor Assays; New York; United States > US; Massachusetts
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3011

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.
Joyce and colleagues analyse tumour–stroma interactions in distinct metastatic microenvironments, and show that cathepsin S promotes brain metastasis by cleaving the JAM-B junctional protein, allowing cancer cells to traverse the blood–brain barrier.