Biology subjects

Healey, J. H.

Publications and source records attributed to Healey, J. H..

4 recordsLinked to original sources

bioRxiv2025

EGR1 Mediates Riluzole-Induced Apoptosis in Osteosarcoma via the Yap/p73-Bax Signaling Axis

Osteosarcoma (OS), although rare, is the most common primary bone cancer, primarily affecting individuals aged 10-30 years. Despite therapeutic advances, survival rates have remained stagnant for decades. Recent studies show that Riluzole, a glutamate receptor antagonist, induces apoptosis in OS cells both in vitro and in vivo. Our previous work demonstrated that Riluzole increases reactive oxygen species (ROS), activating c-Abl kinase, which phosphorylates Yes-associated protein (Yap) at tyrosine 357. This modification promotes nuclear translocation of Yap and interaction with p73, enhancing Bax expression and inducing apoptosis. Early Growth Response 1 (EGR1), a zinc finger transcription factor often linked to apoptosis in other cancers, is significantly downregulated in OS. Here, we investigated the role of EGR1 in Riluzole-mediated apoptosis across OS cell lines and patient-derived xenografts (PDX). In this study, we show that Riluzole upregulates EGR1 expression in all OS cell lines. Chromatin immunoprecipitation followed by qPCR confirmed that EGR1 directly binds to the Bax promoter along with Yap/p73, enhancing Bax expression. Immunohistochemistry of in vivo xenograft tumors from Riluzole-treated mice revealed increased EGR1 and cleaved caspase-3 levels, indicating elevated apoptosis, while reduced NUMA expression suggested diminished tumor proliferation. Together, these findings reveal a novel mechanism where Riluzole promotes apoptosis through upregulation of EGR1, which then cooperates with YAP/p73 to activate Bax expression. These insights establish Riluzole as a promising therapeutic intervention for OS treatment through modulation of the EGR1/Yap/p73/Bax signaling axis.

cancer biology↗

bioRxiv2023

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

cancer biology↗

bioRxiv2022

DNA-functionalized Gold Nanorods for Targeted Triple-modal Optical Imaging and Photothermal Therapy of Triple-negative Breast Cancer

Targeted imaging and therapy for triple-negative breast cancer (TNBC) in the perioperative period are believed to be imperative for better disease management and improved life expectancy. Still, they are not yet available in clinical settings, and only a few nanoparticle-based theranostic agents potentially offer these capabilities. Herein, we develop an innovative class of biocompatible triple-modality nanoprobes (TMNPs) that offer optical imaging using optoacoustic, fluorescence, and surface-enhanced Raman scattering (SERS), as well as photothermal therapy (PTT) with near-infrared (NIR) light. The TMNPs are fabricated by immobilizing positively charged NIR fluorophores on negatively charged DNA-coated gold nanorods (AuNR), then silica encapsulation. The DNA-based design allows the screening of commercially available positively charged NIR fluorophores for the optimum fluorescence and SERS signals. After the design optimization, we functionalize TMNPs with folate groups to target folate receptor1 (FOLR1)-overexpressing TNBC in vitro and in vivo. Our results reveal that TMNPs preferentially accumulate in the FOLR1 positive tumors in TNBC patient-derived xenograft mouse models and show excellent imaging capabilities with all three imaging modalities. Selective exposure of the tumor with NIR laser further shows efficient thermal tissue ablation without causing systemic toxicity. Collectively, TMNP holds great promise for real-time multiplexed imaging of cancer biomarkers and therapeutic capability.

bioengineering↗

bioRxiv2020

Anti-tumor effects of an Id antagonist with no acquired resistance

Id proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket and efficient degradation of the Id proteins. Thus, AGX51 is a first-in-class compound that antagonizes Id proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.

cancer biology↗