Activation of a STAT3/LATS1 Signaling Axis by Folate Receptor α Enables Breast Cancer Cells to Resist Physiological Ferroptotic Stress

Understanding mechanisms that enable cancer cells to evade ferroptotic stress such as that imposed by detachment from extracellular matrix (ECM) is a significant problem that has important ramifications for tumor biology and therapy. We addressed this problem initially by analyzing single cell RNA-seq (scRNA-seq) data obtained from breast tumor organoids that had been treated with the ferroptosis inducer IKE. This bioinformatic analysis revealed that expression of folate receptor (FR) is increased in ferroptosis-resistant sub-populations. Subsequent experiments established a causal role for FR in mediating resistance to ferroptosis triggered by ECM detachment, as well as by IKE treatment. The ability of FR to resist ferroptosis is dependent on the non-canonical activation of STAT3, which has a key role in ferroptosis resistance. Our experimental data revealed that under ECM-detached conditions, ferroptosis resistant cells have increased LATS1, a core kinase in the Hippo pathway. We established that FR regulates LATS1 expression and identified a novel signaling axis that involves the regulation of LATS1 transcription by STAT3 that results in YAP inhibition and the consequent repression of acyl-CoA synthetase long-chain family member 4 (ACSL4), a lipid-modifying enzyme that is essential for ferroptosis. Together, these results highlight an unexpected role for FR in resisting the ferroptotic stress caused by ECM detachment and IKE treatment that is associated with its non-canonical signaling functions.