Despite the significant advances in
cancer research made in recent years, this disease remains one of the leading causes of death worldwide. In part, this is due to the fact that after
therapy, a subpopulation of self-renewing
tumor cells can survive and promote
cancer relapse, resistance to
therapies and
metastasis. Targeting these cancer stem cells (CSCs) is therefore essential to improve the clinical outcome of
cancer patients. In this sense, multi-targeted drugs may be promising agents targeting CSC-associated multifocal effects. We have previously constructed different human
pancreatic ribonuclease (
RNase) variants that are cytotoxic for
tumor cells due to a non-classical
nuclear localization signal introduced in their sequence. These cytotoxic RNases affect the expression of multiple genes involved in deregulated metabolic and signaling pathways in
cancer cells and are highly cytotoxic for multidrug-resistant tumor cell lines. Here, we show that these cytotoxic nuclear-directed RNases are highly selective for tumor cell lines grown in 3D, inhibit CSCs' development and diminish the self-renewal capacity of the CSCs population. Moreover, these human
RNase variants reduce the migration and invasiveness of highly invasive
breast cancer cells and downregulate
N-cadherin expression.