化疗诱导的galectin-1在三阴性乳腺癌中衍生出与EMT相关的耐药持留状态，并对铁死亡诱导剂具有可靶向的脆弱性

Triple-Negative Breast Cancer (TNBC) is the most aggressive and difficult-to-treat disease with high mortality rates. Therapeutic challenges are largely due to limited treatment options, disease heterogeneity, drug resistance, and metastasis to vital organs. Clinical studies established that non-genetic alterations derive chemoresistance and metastasis in TNBC. however, experimental studies investigating residual disease and metastatic recurrence in TNBC are limited. We derived subtype-specific TNBC Drug-Tolerant Persister (DTP) cellular models using taxol and platinum drugs and longitudinally characterized parental, mitotically quiescent and proliferating DTP cellular states to study the molecular basis of post-treatment aggressiveness. We observed that therapeutic agents induced autophagy and dysregulation of ferroptosis regulators including GPX4 and FSP1, irrespective of subtype and EMT largely in basal and luminal androgen receptor-positive TNBC cells. Since these phenotypes are known to be regulated by both intra- and extra-cellular signaling factors we profiled for differentially expressed soluble intracellular and secretome proteome in TNBC DTP cells using label-free quantitative mass spectrometry. Interestingly, we found that soluble factors IGFBP6, SERPINE1 and LGALS1 were among the most upregulated proteins in extracellular protein fractions of DTP cells, LGALS1 was also found significantly high in the cellular fraction. Integrative in-silico analysis of survival and expression data of TNBC patients under treatment accentuated that LGALS1 (Galectin-1) has strong clinical association with adverse prognosis and co-expression with EMT and ferroptosis-related genes. Further, conditioned medium experiment revealed that secretome from proliferating TNBC DTPs was capable of conferring multiple aggressive phenotypes including EMT, migration, invasion, proliferation, antioxidant pathway deregulation, autophagy in parental TNBC cells. These changes were collaborated with an increased activation of pSTAT3, pSrc and MAP kinase signaling pathways. Moreover, genetic and pharmacological targeting of Galectin-1 in TNBC DTP cells significantly attenuation proliferation, EMT, migration and invasion properties, with an increased susceptibility to ferroptosis inducers. Further, Galectin-1 knockdown resulted in downregulation of GPX-4 and FSP-1 in a NRF2-dependent manner, highlighting the therapeutic potential of targeting Galectin-1 in controlling EMT and inducing ferroptotic cell death. Most importantly, considering that tumor-secreted Galectin-1 can be detected in the blood it may serve as a theranostic biomarker for therapy resistance and poor prognosis as well as potential therapeutic target for overcoming chemo-tolerance and metastasis in TNBC patients.