Research

Cathepsins B and X in breast cancer stem cells – molecular targets and relevance for antitumor therapy

Code:

J3-3071

Range:

01. October 2021 - 30. September 2024

Range:

0,12 FTE

Leader:

Janko Kos

Field:

3.04 Medical Sciences/Oncology

Abstract:

Despite advances over the past years the treatment of breast cancer is still facing many challenges, among them overcoming cancer recurrence and avoiding therapy resistance are the main goals in the aim to improve patients’ status. Failure in antitumor therapy has been, among the phenotypically and functionally heterogenous population of cells with different degree of differentiation within tumors, mainly attributed to cancer stem cells (CSCs). CSCs represent a small subset of cells with a tumorigenic potential that are resistant to the convenient antitumor therapies and can give rise to a disease relapse. Therefore, to improve the effectiveness of treatment for breast cancer and patient’s survival, new approaches that would, in addition to differentiated cells, be effective also towards CSCs are urgently needed. Targeting proteolytic enzymes associated with tumor progression such as cathepsins B and X deserved an attention in CSCs directed therapy research. In cancer the expression and activity of these redundant lysosomal cysteine carboxypeptidases have an important role in degradation of extracellular matrix, tumor invasion, migration, metastasis and angiogenesis, with increased expression associated with less differentiated cell phenotype and CSCs. Cathepsins B and X can be selectively regulated by small molecular inhibitors. It was demonstrated that these inhibitors may change the phenotype of CSCs towards more differentiated cells and impair tumor progression. Since cathepsins B and X function within highly regulated proteolytic networks the understanding of their effect on downstream targets in CSCs is needed. Thus, in the present project we aim to identify molecular targets of cathepsins B and X in breast CSCs and evaluate their relevance for antitumor therapy. Furthermore, our goal is to identify and evaluate the involvement of cathepsins B and X in key signaling pathways crucial for induction and maintenance of stemness. Interactions between cathepsins B and X and their molecular targets will be evaluated regarding functional properties of breast CSCs in in vitro models of tumor cell migration and invasion as well as in vivo on tumor mice models. This will importantly contribute to understanding the relevance of proteolytic enzymes in breast CSCs maintenance and differentiation. Taken together, outcomes of our proposed project will represent important contribution in development of new strategies that could overcome limitations and improve clinical outcome of current antitumor therapies.