p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas

Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction

Biolistic Delivery of MOF-Protected Liposomes

Needle-and-syringe-based delivery has been the commercial standard for vaccine administration to date. With worsening medical personnel availability, increasing biohazard waste production, and the possibility of cross-contamination, we explore the possibility of biolistic delivery as an alternate skin-based delivery route. Delicate formulations like liposomes are inherently unsuitable for this delivery model as they are delicate biomaterials incapable of withstanding shear stress. When encapsulated within a crystalline and rigid coating made of zeolitic imidazolate frameworks, the liposomes are not only protected from thermal stress but also shear stress. The protection from shear stress is crucial, especially for formulations with cargo encapsulated inside the lumen of the liposomes. Moreover, the coating provides the liposomes a solid, rigid exterior which allows the particles to penetrate the tissue model and porcine tissue effectively

Metal–Organic Framework Encapsulated Whole-Cell Vaccines Enhance Humoral Immunity against Bacterial Infection

International audienceThe increasing rate of resistance of bacterial infection against antibiotics requires next generation approaches to fight potential pandemic spread. The development of vaccines against pathogenic bacteria has been difficult owing, in part, to the genetic diversity of bacteria. Hence, there are many potential target antigens and little a priori knowledge of which antigen/s will elicit protective immunity. The painstaking process of selecting appropriate antigens could be avoided with whole-cell bacteria; however, whole-cell formulations typically fail to produce long-term and durable immune responses. These complications are one reason why no vaccine against any type of pathogenic E. coli has been successfully clinically translated. As a proof of principle, we demonstrate a method to enhance the immunogenicity of a model pathogenic E. coli strain by forming a slow releasing depot. The E. coli strain CFT073 was biomimetically mineralized within a metal-organic framework (MOF). This process encapsulates the bacteria within 30 min in water and at ambient temperatures. Vaccination with this formulation substantially enhances antibody production and results in significantly enhanced survival in a mouse model of bacteremia compared to standard inactivated formulations

PhotothermalPhage: A Virus-Based Photothermal Therapeutic Agent

ABSTRACT: Virus-like particles (VLPs) are multifunctional nanocarriers that mimic the architecture of viruses. They can serve as a safe platform for specific functionalization and immunization, which provides benefits in a wide range of biomedical applications. In this work, a new generation immunophotothermal agent is developed that adjuvants photothermal ablation using a chemically modified VLP called bacteriophage Qβ. The design is based on the conjugation of near-infrared absorbing croconium dyes to lysine residues located on the surface of Qβ, which turns it to a powerful NIR-absorber called Photothermal Phage. This system can generate more heat upon 808 nm NIR laser radiation than free dye and possesses a photothermal efficiency comparable to gold nanostructures, yet it is biodegradable and acts as an immunoadjuvant combined with the heat it produces. The synergistic combination of thermal ablation with the mild immunogenicity of the VLP leads to effective suppression of primary tumors, reduced lung metastasis, and increased survival time

p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas

Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction