Biology subjects

Perryman, L.

Publications and source records attributed to Perryman, L..

4 recordsLinked to original sources

bioRxiv2025

LOX inhibition disrupts a collagen-integrin-MYC axis as a translatable targeting strategy in invasive lobular carcinoma

Invasive lobular carcinoma (ILC) accounts for 15% of breast cancers yet lacks specific therapy because ILCs are underrepresented in clinical trials and preclinical models are lacking. We established intraductal xenograft models to test whether the clinical pan-lysyl-oxidase PXS-5505, now in phase trials for myelofibrosis can exploit the collagen-rich matrix dependency created by CDH1 loss. PXS-5505 remodels fibrillar collagen, and halts tumor expansion and metastatic seeding across ER+ and triple negative models without systemic toxicity. Genome-wide CRISPR screens reveal ITGAV and ITGB5 as synthetic lethal partners of CDH1 and LOX inhibition downregulates their expression together with MYC, NF-{kappa}B, and AP-1 transcriptional programmes. Collagen fibre density/alignment, and MYC/AP-1 gene signatures serve as pharmacodynamic readouts of drug activity. These data uncover a tractable ECM-integrin-MYC axis in ILC and nominate PXS-5505, alone or with endocrine therapy, for window of opportunity trials in this understudied breast cancer subtype. One Sentence SummaryTargeting matrix remodelling in ILC inhibits ILC progression and alters multiple molecular endpoints, providing a translatable therapeutic strategy for this understudied subtype that requires better treatments.

cancer biology↗

bioRxiv2025

Matrix structure and microenvironment dynamics correlate with chemotherapy response in ovarian cancer

Elevated extracellular matrix (ECM) in the tumor microenvironment (TME) is associated with chemoresistance and poor prognosis. We hypothesized that modifying the ECM may enhance response to chemotherapy. We measured chemotherapy-induced changes in the TME of two mouse models of high-grade serous ovarian cancer (HGSOC) that differed in chemotherapy response. Treatment of the chemo-sensitive tumors triggered dynamic transcriptional ECM and immune changes and structural modifications of ECM proteins. These changes, observed over twenty-days post-chemotherapy, had relevance to HGSOC patient responses to chemotherapy. Integrating transcriptomics with ECM structure metrics, we identified ECM targets, including lysyl oxidase (LOX), that might enhance chemotherapy in less responsive mouse tumors. Given alone or in combination with chemotherapy, a pan-LOX inhibitor (PXS-5505) modulated fibroblast and immune cell distribution and reduced tumor stiffness in HGSOC chemo-resistant mouse tumors. Moreover, pre-treatment with PXS-5505 improved response to chemotherapy. We conclude that pretreatment with ECM targeting agents may improve response to chemotherapy, by altering ECM structure and immune responses.

cancer biology↗

bioRxiv2024

Cleavage of the vascular matrix attracts glioblastoma cells to infiltrate the brain parenchyma

BackgroundGlioblastoma is a highly aggressive brain cancer and, unlike many other cancers types, the median survival for patients after treatment (14.6 months) has barely improved in the last 20 years. Infiltrative growth into the surrounding brain parenchyma facilitates tumor recurrence and ultimately the death of the patient - novel therapies targeting this process are desperately needed. Lysyl oxidase inhibition has been shown to decrease invasive growth in a variety of solid tumours and is a potential therapy for glioblastoma patients. MethodsGenes highly expressed in the mesenchymal subtype of glioblastoma were analyzed in a data set from the Cancer Genome Atlas and tissue microarrays. Two patient-derived human glioblastoma stem cell lines were used to assess the involvement of lysyl oxidase (LOX). The effect of LOX on infiltration was examined in an organotypic brain slice assay and in an orthotopic mouse model. Chemotactic assays, protease and cleavage arrays were used to assess the underlying mechanism behind LOX-mediated infiltration. The orthotopic model was used to evaluate potential clinical utility of targeting LOX in glioblastoma. ResultsLOX is overexpressed in the mesenchymal glioblastoma subtype and strongly associated with poor patient survival. LOX expression upregulates MMP7 expression, which subsequently cleaves the vascular matrix resulting in increased chemotaxis of glioblastoma cells. ConclusionsWe have uncovered a novel mechanism of glioblastoma infiltration and suggest that targeting LOX represent an effective therapeutic approach blocking glioblastoma infiltration. Importance of the studyThe ability of glioblastoma cells to infiltrate the surrounding normal brain tissue facilitates their evasion of current therapies, leading to tumor recurrence and ultimately the death of the patient. To improve targeted therapies for glioblastoma patients we need to understand the molecular mechanisms of glioblastoma cell infiltration and how cells interact with the unique microenvironment of the brain. We have identified a novel mechanism whereby tumor-derived LOX mediates chemotaxis of glioblastoma cells to the laminin rich perivascular niche, enabling infiltrative growth. Inhibiting this infiltrative pathway is a potential anti-invasive therapy that is desperately needed for glioblastoma patients.

cancer biology↗

bioRxiv2023

Accurate quantification of lysyl oxidase concentration in human tissue

The family of Lysyl oxidase enzymes play fundamental roles in the formation of the extracellular matrix, through catalyzing the crosslinking of collagen and elastin fibers. Lysyl oxidase (LOX) -- one of the 5 family members (LOX, LOXL1-4), is a disease biomarker, with blood concentration positively correlating with progression of fibrosis or cancer. An accurate quantification of LOX concentration can support diagnosis, monitoring of disease progression or treatment success. However, reported LOX concentrations in human blood are inconsistent. Therefore, a novel, high-throughput and sensitive digital enzyme-linked immunosorbent assay was developed using two validated and selective human anti-LOX antibodies and single molecule array technology. Both, the 56 kDa pro-form and the 32 kDa active form can be accurately measured from recombinant and native protein. The serum LOX concentration correlated with LOX activity measured in the same platform using a bio-probe. The usefulness of this technology was demonstrated in serum from bladder cancer patients wherein LOX concentration was significantly higher compared to the healthy subjects. This study demonstrates the validation and use of a sensitive and accurate method for measuring LOX concentration in human samples. This novel method may be superior than some commercially available enzyme-linked immunosorbent assay kits for accurate measurement of LOX concentrations in clinical settings.

molecular biology↗