Carrasco, G. | bioRxiv Science

bioRxiv2025

FAK inhibitor treatment systemically regulates the glioblastoma immune environment via blocking monocyte trafficking

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults with dismal survival rates, and current therapies, including most immunotherapies, are not efficacious due to the highly immunosuppressive microenvironment. Studies in other solid cancers report that impairment of the integrin effector pathway involving focal adhesion kinase (FAK) can promote anti-tumour immune responses. Therefore, we set out to address whether, and if so how, suppressing FAK function may influence GBM by using both tumour cell-specific FAK gene deletion and systemic delivery of a clinically relevant FAK kinase inhibitor (FAKi) VS-4718 in an orthotopic murine stem cell model of GBM. We found that treatment with the FAKi, but not tumour cell-specific FAK gene deletion, resulted in GBM clearance and improved survival. This was dependent on adaptive immunity, and tumour-infiltrating T cells in FAKi-treated tumours displayed increased cytotoxic potential and reduced exhaustion. We also found a significant reduction in immuno-suppressive peripherally-derived macrophages and FAKi treatment caused sequestration of inflammatory monocytes within the bone marrow, resulting in impaired monocyte trafficking to tumours as judged by adoptive transfer. This is due to suppression of key adhesion and migration signalling through 4{beta}1 integrin and CX3CR1 in peripheral monocytes. Our work here describes a previously unidentified role for FAK in trafficking of peripheral suppressive macrophages to GBM tumours, reducing T cell exhaustion and promoting anti-tumour immunity. This highlights a new way in which systemic FAK inhibitors can be used to provide a beneficial immune modulatory strategy for the treatment of GBM.

immunology↗

bioRxiv2024

Life on the edge: microbial diversity, resistome, and virulome in soils from the Union Glacier cold desert

The high-latitude regions of Antarctica remain among the most remote, extreme, and least explored areas on Earth. Despite the highly restrictive conditions, microbial life has been found in these environments, although with limited information on their genetic properties and functional capabilities. Moreover, the accelerated melting of the Antarctic permafrost, the increasing exposure of soils, and the growing human transit pose the question of whether these environments could be a source of microbes or genes that could emerge and cause global health problems. In this line, although a high bacterial diversity and autochthonous multidrug-resistant bacteria have been found in soils of the Antarctic Peninsula, we still lack information regarding the resistome of areas closer to the South Pole. Moreover, no previous studies have evaluated the pathogenic potential of microbes inhabiting Antarctic soils. In this work, we combined metagenomic and culture-dependent approaches to investigate the microbial diversity, resistome, virulome, and mobile genetic elements (MGEs) in soils from Union Glacier, a high-latitude cold desert in West Antarctica. Despite the low organic matter content, diverse bacterial lineages were found, predominating Actinomycetota and Pseudomonadota, with limited archaeal and fungal taxa. We recovered more than 80 species-level representative genomes (SRGs) of predominant bacterial taxa and the archaeon Nitrosocosmicus sp. Diverse putative resistance and virulence genes were predicted among the SRGs, metagenomic reads, and contigs. Furthermore, we characterized bacterial isolates resistant to up to 24 clinical antibiotics, mainly Pseudomonas, Arthrobacter, Plantibacter, and Flavobacterium. Moreover, some isolates produced putative virulence factors, including siderophores, pyocyanins, and exoenzymes with hemolytic, lecithinase, protease, and DNAse activity. This evidence uncovers a largely unexplored resistome and virulome hosted by deep Antarcticas soil microbial communities and the presence of bacteria with pathogenic potential, highlighting the relevance of One Health approaches for environmental surveillance in the white continent. HIGHLIGHTS-Union Glacier soils host a microbial community dominated by bacteria, mainly from the phylum Actinomycetota. -Archaea from the Nitrosocosmicus genus (family Nitrosphaeraceae) were ubiquitously detected. -Although extreme and remote, these soils host multidrug-resistant and potentially pathogenic bacteria. Some were cultured and tested in vitro. -Metagenomes and species-level representative genomes revealed diverse putative resistance and virulence genes. -Part of the putative antimicrobial resistance genes and virulence factors could be associated with mobile elements in bacterial genomes.

microbiology↗