ABSTRACT
Frequent metastatic relapses in Triple-Negative Breast Cancer (TNBC) patient with residual disease is a clinical challenge, largely due to tumor heterogeneity and absence of strategies that target proliferating chemo-tolerant cells. Here, we longitudinally modeled cellular state transitions from dormant drug-tolerant persister (DTP) into proliferating drug-tolerant persister (PDTP) in cells representing all TNBC subtypes. Combining subcellular imaging with phenotypic and biochemical assays, we identified distinct and converged spectrums of alterations in TNBC PDTPs. We show that PDTPs retain acquired resistance with increased invasion potential. Moreover, Basal-Like DTPs enter into a non-reversible mesenchymal state while, luminal androgen receptor-positive gained partial-Epithelial-to-Mesenchymal Transition (EMT) with vimentin upregulation. PDTP state dwells on high autophagy with reduced glutathione and GPX4 levels, rendering it vulnerable to autophagy suppression and ferroptosis. Interestingly, we find that GPX4 negatively regulates EMT and autophagy in TNBC, and inverse correlation of GPX4-VIM expression along with autophagy genes predict survival in TNBC patients undergoing chemotherapy.
Competing Interest Statement
The authors have declared no competing interest.
