Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• Breast cancer stem cells (CSCs) drive tumor heterogeneity and treatment resistance, particularly in triple-negative breast cancer.
• Targeting CSCs is challenging due to their metabolic adaptability and lack of defined regulatory mechanisms.
• Transcription factor EB (TFEB) has been implicated in cellular metabolism.

Purpose of the Study:

• To investigate the role of TFEB in regulating CSC metabolism and response to metabolic stress.
• To elucidate the mechanisms by which TFEB influences CSC properties and survival.

Main Methods:

• TFEB knockdown (KD) in CSCs.
• In vitro mammosphere formation assays and in vivo tumor initiation studies.
• Analysis of CSC markers (CD44high/CD24low), TFEB nuclear translocation, unfolded protein response (UPR) mediators (BiP/HSPA5, CHOP), and autophagy.

Main Results:

• TFEB KD inhibited CSC self-renewal, mammosphere formation, and tumor growth.
• TFEB KD reduced the proportion of CD44high/CD24low cells.
• 2-deoxy-D-glucose (2-DG) treatment induced TFEB nuclear translocation and UPR, which was blunted by TFEB KD.
• TFEB KD attenuated 2-DG-induced autophagy, suggesting TFEB promotes CSC survival under metabolic stress.

Conclusions:

• TFEB plays a critical role in modulating the metabolic stress response of CSCs in triple-negative breast cancer.
• TFEB regulates CSCs through mechanisms involving autophagy and the unfolded protein response (UPR).
• TFEB represents a potential therapeutic target for overcoming treatment resistance in triple-negative breast cancer.