Biology subjects

Mercurio, A. M.

Publications and source records attributed to Mercurio, A. M..

5 recordsLinked to original sources

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↗

bioRxiv2025

Therapeutic delivery of albumin-binding siRNA targeting IRS2 to diverse cell types reduces mammary tumor growth

Oligonucleotide therapeutics are a new class of drugs that enable robust and sustained modulation of gene expression. However, achieving efficient delivery of siRNAs to tumors is a challenge for therapy. Here, we demonstrate that fully chemically modified siRNAs conjugated with an albumin-binding dendrimer are efficiently delivered to both neoplastic and stromal/immune cells within primary TNBC mammary tumors. siRNAs were designed to selectively target IRS2, a signaling adaptor of insulin and insulin-like growth factor signaling that has been implicated in aggressive breast cancers. These siRNAs reduced Irs2 expression in tumor and stromal cells without causing hyperglycemia, resulting in reduced tumor growth that was associated with decreased vascularization and alterations in macrophage polarization and the expression of EMT proteins. This work demonstrates that siRNAs can be delivered to neoplastic and specific stromal populations in mammary tumors and that they can effectively and specifically silence a driver of aggressive breast cancer.

cancer biology↗

bioRxiv2025

Resistance to Radiation Enhances Metastasis by Altering RNA Metabolism

The cellular programs that mediate therapy resistance are often important drivers of metastasis, a phenomenon that needs to be understood better to improve screening and treatment options for cancer patients. Although this issue has been studied extensively for chemotherapy, less is known about a causal link between resistance to radiation therapy and metastasis. We investigated this problem in triple-negative breast cancer (TNBC) and established that radiation resistant tumor cells have enhanced metastatic capacity, especially to bone. Resistance to radiation increases the expression of integrin {beta}3 (ITG{beta}3), which promotes enhanced migration and invasion. Bioinformatic analysis and subsequent experimentation revealed an enrichment of RNA metabolism pathways that stabilize ITG{beta}3 transcripts. Specifically, the RNA binding protein heterogenous nuclear ribonucleoprotein L (HNRNPL), whose expression is regulated by Nrf2, mediates the formation of circular RNAs (circRNAs) that function as competing endogenous RNAs (ceRNAs) for the family of let-7 microRNAs that target ITG{beta}3. Collectively, our findings identify a novel mechanism of radiation-induced metastasis that is driven by alterations in RNA metabolism.

cancer biology↗

bioRxiv2024

MYC and p53 alterations cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer

Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted and immunotherapies. Whether genetic alterations acquired during the evolution of CRPC impact immune and immunotherapy responses is largely unknown. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which by signaling through VEGFR2 expressed on CD8+ T cells, could directly inhibit T cell activity. Targeting VEGF-VEGFR2 signaling in vivo led to CD8+ T cell-mediated tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1, and in combination with PD-L1 immune checkpoint blockade produced anti-tumor efficacy in multiple preclinical CRPC mouse models. Thus, our results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC. SignificanceThough immune checkpoint blockade (ICB) therapies can achieve curative responses in many treatment-refractory cancers, they have limited efficacy in CRPC. Here we identify a genetic mechanism by which VEGF contributes to T cell suppression, and demonstrate that VEGFR2 blockade can potentiate the effects of PD-L1 ICB to immunologically treat CRPC.

cancer biology↗