A Nuclear-Directed Ribonuclease Variant Targets Cancer Stem Cells and Inhibits Migration and Invasion of Breast...

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Cancer remains a leading cause of death globally, partly due to therapy-resistant cancer stem cells (CSCs) that drive relapse and metastasis.
• Targeting CSCs is crucial for improving cancer patient outcomes.
• Multi-targeted drugs show promise for addressing CSC-associated multifocal effects.

Purpose of the Study:

• To evaluate the efficacy of novel human pancreatic ribonuclease (RNase) variants in targeting cancer stem cells (CSCs).
• To investigate the impact of these engineered RNases on CSC self-renewal, migration, and invasiveness.

Main Methods:

• Construction of human pancreatic RNase variants with a non-classical nuclear localization signal.
• Assessment of RNase cytotoxicity against multidrug-resistant tumor cell lines and 3D tumor models.
• Evaluation of CSC development and self-renewal capacity inhibition.
• Analysis of effects on breast cancer cell migration, invasiveness, and N-cadherin expression.

Main Results:

• Engineered RNases exhibit high cytotoxicity towards tumor cells, including multidrug-resistant lines.
• These RNases selectively target 3D-grown tumor cells and inhibit CSC development.
• The RNase variants diminish CSC self-renewal capacity.
• Treatment with RNase variants reduces the migration and invasiveness of highly invasive breast cancer cells, accompanied by N-cadherin downregulation.

Conclusions:

• Cytotoxic, nuclear-directed human RNase variants effectively target and inhibit cancer stem cells.
• These RNases demonstrate potential as a novel therapeutic strategy against cancer relapse, metastasis, and therapy resistance.
• The findings highlight the therapeutic promise of multi-targeted RNase agents for improving cancer treatment efficacy.