Impact of cancer associated fibroblasts-derived cathepsin B on breast cancer progression

Tumors arise in a complex ecosystem gover ned by interactions established between cancer cells and the microenvironment. This one
is constituted on one side by a multitude of different non-cancerous cell types (e.g.: stromal and immune cells) and on the other side
by components of the extracellular matrix. During cancerogenesis fibroblasts are activated and differenciated into cancer associated
fibroblasts (CAFs). Nevertheless, the precise functions of CAFs in cancer progression are not fully understood. Among proteases implicated
in both ECM remodeling and cancer progression, cathepsin B (Ctsb), a lysosomial cystein protease, has been detected in cancer
cells and in tumor-associated macrophages. Ctsb expression is associated with a poor prognosis in breast cancer patients. However, the
contribution of CAF-derived Ctsb to tumor progression is unknown.
By using the MMTV-PyMT mouse model of breast cancer, our preliminary data reveal that CAFs express Ctsb at higher levels than cancer
cells. Our data show that Ctsb deficiency impairs the capacity of CAFs to interact with collagen fibers and strongly diminishes the migration
of CAFs in a 3D spheroid model. Further more, we demonstrate that the invasion of Ctsb-/- CAFs is restored upon addition of conditioned
medium collected from WT CAFs but Further more, the invasion of Ctsb-/- CAFs is restored upon addition of conditioned medium
collected from wild-type (WT) CAFs but also by durotaxis or by deletion of Cathepsin Z (Ctsz). Collectively these data suggest that Ctsb
represents a key regulator of the complex cross-talk established between CAFs, the ECM and cancer cells.