Dimitrov, B. S. | bioRxiv Science

bioRxiv2026

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.

cancer biology↗

bioRxiv2026

Folate Receptor α Contributes to Radiation Resistance in Neuroendocrine Prostate Cancer by Regulating Redox Homeostasis

Ionizing radiation can be an effective therapy for prostate cancer. Unfortunately, however, more aggressive prostate cancers such as neuroendocrine prostate cancer (NEPC) are often radiation resistant, which contributes to their high degree of morbidity and mortality. In this study, we used an unbiased approach to identify novel mechanisms that contribute to resistance to radiation and that are associated with neuroendocrine differentiation. Specifically, we compared the expression of cell surface proteins by mass spectrometry in prostate cancer cell lines that had been either untreated or treated with radiation to induce resistance, a process that also promotes neuroendocrine differentiation. Among the proteins identified by this screen, we focused on folate receptor (FR) because of its known biological functions and the fact that it is a validated therapeutic target. Our data reveal that FR has a causal role in enabling prostate cancer cells to resist radiation. Importantly, we also demonstrate that the expression of FR is regulated by HIF-1, which also has a causal role in radiation resistance and neuroendocrine differentiation. Given that the ability of cells to resist damage and death in response to ionizing radiation depends largely on their ability to buffer the substantial increase in reactive oxygen species (ROS) that is generated by radiation, we also demonstrate that the folate-FR axis promotes radiation resistance by sustaining intracellular glutathione levels that buffer this increase in ROS. In summary, the data reported here highlight a novel role for FR in resistance to ionizing radiation that is intimately associated with the hypoxic microenvironment of NEPC and the ability of the folate-FRa axis to maintain redox homeostasis.

cancer biology↗