Biology subjects

Loftus, A. E. P.

Publications and source records attributed to Loftus, A. E. P..

5 recordsLinked to original sources

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↗

bioRxiv2025

Tissue scarring provides a biomechanical framework to promote mammalian bile duct regeneration through the activation of integrin-SRC/FAK signalling.

Following chronic injury, the adult mammalian bile duct regenerates by forming new branches, essentially replumbing the ductular system to overcome blockages and breaks. To regenerate effectively, biliary epithelial cells (BECs) receive a range of pro-mitogenic signals from myofibroblasts, which concurrently deposit a collagen-rich scar around the duct as it regrows. Despite epithelial regeneration and scarring occurring side-by-side, whether the deposition of scar tissue regulates ductular regeneration per se remains unclear. By inducing ductular fibrosis and regeneration in vivo, we show that the formation of collagen-I-rich scars around regenerating ducts changes the local biomechanical properties of these tissues, promoting the growth of ducts. Critically, this changing structural landscape is perceived by a spatially restricted population of biliary epithelial cells which forms a "leading-tip" of integrin-2-high cells. This leading-tip undergoes partial-EMT-type reprogramming, allowing it to become migratory and coordinate ductular regeneration. We show that this process is directly driven through an integrin-2-SRC/FAK signalling axis; thereby connecting epithelial regeneration directly to the changing fibrotic environment in chronic ductular disease. HighlightsO_LIChronic liver disease results in the formation of stiff, collagen scars around ducts. C_LIO_LINew ducts acquire high levels of integrin-2 which is spatially localised to a "leading-tip", which loses epithelial features. C_LIO_LIIntegrin-2{beta}1-SRC/FAK signalling regulates ductular migration by linking changes in the bio-structural composition of the liver with ductular cells. C_LI

cell biology↗

bioRxiv2023

A novel ILK/STAT3 pathway controls plasticity in a neural stem cell model of glioblastoma.

Glioblastomas (GBM) are driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drives tumour progression and therapeutic resistance. Here we show that the nodal extracellular matrix-cell adhesion protein integrin-linked kinase (ILK; a pseudokinase), is a key determinant of phenotypic plasticity and the mesenchymal-like, invasive cell state in mouse GBM stem cells. We found that a novel ILK-STAT3 signalling pathway is required for plasticity that enables the transition of GBM stem cells to an astrocyte-like state both in vitro and in vivo. GBM cells genetically depleted of ILK become predominantly stabilised in a transcriptionally-defined progenitor-like state that is characterised by lack of response to differentiation cues and constitutive proliferation. Loss of ILK or interference with STAT3 impairs differentiation potential, reducing phenotypic plasticity of tumour cell populations; additionally, ILK loss causes a mesenchymal- to epithelial-like morphological transition and suppression of malignancy-associated features. Our work defines ILK as a central regulator of multiple GBM phenotypes including phenotypic plasticity and mesenchymal state.

cancer biology↗

bioRxiv2021

Mena regulates the LINC complex to control actin-nuclear lamina associations, trans-nuclear membrane signalling and cancer gene expression

Interactions between cells and the extracellular matrix, mediated by integrin adhesion complexes (IACs), play key roles in cancer progression and metastasis. We investigated systems-level changes in the integrin adhesome during metastatic progression of a patient-derived cutaneous squamous cell carcinoma (cSCC), and found that the actin regulatory protein Mena is enriched in IACs in metastatic cSCC cells. Mena is connected within a subnetwork of actin-binding proteins to the LINC complex component nesprin-2, with which it interacts and co-localises at the nuclear envelope of metastatic cells. Moreover, Mena potentiates the interactions of nesprin-2 with the actin cytoskeleton and the nuclear lamina. CRISPR-mediated Mena depletion causes altered nuclear morphology, reduces tyrosine phosphorylation of the nuclear membrane protein emerin and downregulates expression of the immunomodulatory gene PTX3 via the recruitment of its enhancer to the nuclear periphery. We have uncovered an unexpected novel role for Mena at the nuclear membrane, where it controls the LINC complex, nuclear architecture, chromatin repositioning and cancer gene expression. This is the first description of an adhesion protein regulating gene transcription via direct signalling across the nuclear envelope. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/458340v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@14e2251org.highwire.dtl.DTLVardef@af341corg.highwire.dtl.DTLVardef@8624dforg.highwire.dtl.DTLVardef@deeb50_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Characterisation of a nucleo-adhesome

In addition to central functions in cell adhesion signalling, integrin-associated proteins have wider roles at sites distal to adhesion receptors. In experimentally defined adhesomes, we noticed that there is clear enrichment of proteins that localise to the nucleus, and conversely, we now report that nuclear proteomes contain a class of adhesome components that localise to the nucleus. We here defined a nucleo-adhesome, providing experimental evidence for a remarkable scale of nuclear localisation of adhesion proteins, establishing a framework for interrogating nuclear adhesion protein functions. In adding to nuclear FAKs known roles in regulating transcription, we now show that nuclear FAK regulates expression of many adhesion-related proteins that localise to the nucleus and that nuclear FAK binds to the adhesome component and nuclear protein Hic-5. FAK and Hic-C work together in the nucleus, co-regulating a subset of genes transcriptionally. We describe the first nucleo-adhesome using a squamous cancer cell model, and demonstrate the new principle that there are nuclear adhesion protein subcomplexes that cooperate to control transcription. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/458428v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1c841ceorg.highwire.dtl.DTLVardef@586a75org.highwire.dtl.DTLVardef@b54439org.highwire.dtl.DTLVardef@921537_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗