A novel CD44-targeting aptamer recognizes chemoresistant mesenchymal stem-like TNBC cells and inhibits tumor growth

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Triple-negative breast cancer (TNBC) presents a therapeutic challenge due to limited targeted treatments and high recurrence rates.
• The nuclease-resistant RNA sTN58 aptamer was previously developed for selective TNBC cell targeting.

Purpose of the Study:

• To identify the cellular target of the sTN58 aptamer.
• To evaluate the therapeutic potential of sTN58 in chemoresistant TNBC models.

Main Methods:

• Affinity purification using sTN58 aptamer to isolate binding targets from TNBC cell membranes.
• Mass spectrometry and aptamer binding assays to identify the target.
• In vitro assays assessing invasive growth and tube formation.
• In vivo studies in mice with orthotopic TNBC xenografts.

Main Results:

• CD44 was identified as the specific cellular target of the sTN58 aptamer.
• sTN58 binding to CD44 inhibited invasive growth and hyaluronic acid-dependent tube formation in chemoresistant TNBC cells.
• In vivo administration of sTN58 demonstrated significant tumor growth inhibition and reduced lung metastasis in orthotopic TNBC models.

Conclusions:

• CD44 is a key driver of aggressiveness and stem-like plasticity in chemoresistant TNBC.
• The sTN58 aptamer effectively targets CD44-overexpressing TNBC cells.
• sTN58 shows significant potential as a therapeutic agent for TNBC, particularly in targeting CD44.