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

Abstract

ABSTRACTBreast Cancer Stem Cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in Triple-Negative Breast Cancer (TNBC). CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formationin vitroand tumor initiation/growthin vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24lowcells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven UPR mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in TNBC.Financial SupportThis work was supported by CPRIT Grant RR160093 (to S.G. Eckhardt), CPRIT Grant RP210088 (to K.N. Dalby), UT College of Pharmacy Non-discretionary Funds (to C. Van Den Berg), and UT Graduate Continuing Fellowship (to M. Soleimani).