Abstract 4674: Activation of a STAT3/LATS1 signaling axis by folate receptor alpha enables breast cancer cells to resist ferroptosis

Abstract Dynamic changes occurring in the tumor microenvironment that carcinoma cells encounter during their progression can trigger ferroptosis, a form of cell death characterized by the iron-dependent lipid peroxidation of cell membranes. This phenomenon is exacerbated during metastasis as tumor cells in circulation are exposed to conditions of matrix-detachment, oxidative stress and high iron concentration. Many tumor cells withstand these conditions to survive, which suggests they have acquired mechanisms to resist ferroptotic stimuli. Our goal in this study was to identify specific cell surface proteins expressed on breast cancer cells that promote ferroptosis resistance since such proteins can serve as therapeutic targets. To achieve this goal, we used an unbiased approach that involved analysis of single-cell RNA sequencing data (scRNA-seq) that we obtained from an organoid derived from a breast cancer patient that was exposed to a ferroptosis-inducing drug, imidazole ketone erastin (IKE). Differential gene expression analysis of this scRNA seq revealed that folate receptor α (FRα) is significantly expressed in ferroptosis non-responder populations. Subsequently, we demonstrated a causal role for FRα in promoting resistance to ferroptosis induced by both IKE and matrix detachment in breast cancer cell lines (CAL51 and T47D). We verified the ability of FRα to activate STAT3 and observed that STAT3 drives ferroptosis resistance in our model. To understand how STAT3 promotes ferroptosis resistance, we identified LATS1, a key regulator of Hippo signaling that phosphorylates and inactivates YAP and TAZ. Using chromatin immunoprecipitation, we observed that STAT3 binds to the LATS1 promoter region and that inhibition of STAT3 reduces LATS1 gene and protein expression. We also found that STAT3-mediated regulation of LATS1 inhibits YAP, which is known to promote ferroptosis sensitivity. To investigate a mechanism for how inhibition of YAP by STAT3/LATS1 contributes to ferroptosis resistance, we focused on the ability of YAP to regulate Acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that triggers ferroptosis by remodeling lipid membranes in cells. Our data revealed that STAT3 and LATS1 have a causal role in inhibiting YAP-mediated induction of ASCL4 expression. Together, these data highlight a novel role for FRα in promoting ferroptosis resistance by a mechanism that is dependent on LATS1. Ongoing studies are aimed at investigating the ability of FRα and LATS1 to enhance metastasis by promoting ferroptosis resistance. This work also suggests that FRα could be an effective therapeutic target for mitigating metastatic breast cancer. Citation Format: Prajakta Prasad Ambegaokar, Hira Goel, Arthur M. Mercurio. Activation of a STAT3/LATS1 signaling axis by folate receptor alpha enables breast cancer cells to resist ferroptosis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4674.