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 tumor microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analyzed tumor-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 tumor cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration via 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.

Pericellular proteolysis in cancer

“…As these representative examples indicate, proteases can promote invasion and metastasis to multiple organ sites through a plethora of different molecular mechanisms. Notably, levels of protease expression correlate with organ-specific metastasis in patients (Lu et al 2009;Sevenich et al 2014), revealing both potential prognostic markers and therapeutic targets.…”

Blood-brain Barrier Remodeling during Brain Metastasis Formation

“…Also cathepsin S has been shown to specifically mediate BBB transmigration of breast tumor cells via proteolytic processing of the junctional adhesion molecule (JAM)-B. Importantly, genetic or pharmacological inhibition of cathepsin S significantly impaired experimental brain metastasis (44). Specific adhesion molecules have also been found to facilitate tumor cell migration to the brain.…”

Darwinian Principles in Cancer Therapy

“…the part of a tumour that does not consist of mutated sub-clones, provides a much more genetically stable focus that is far less likely to develop resistances towards treatment. 43 Restoration of 'normal' microenvironment can prevent tumour progression and even formation, 44,45 which is of particular interest if one considers the 'premetastatic niche'. While the underlying dynamics of niche formation seem to be not without controversy, 46 it appears that alterations of the microenvironment at a future site of metastasis can precede the arrival of mutant cancer cells.…”