Biology subjects

Gartland, A.

Publications and source records attributed to Gartland, A..

4 recordsLinked to original sources

bioRxiv2023

The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis

RNA-binding proteins (RBPs) are emerging as important regulators of pathogenesis, including cancer. Here we reveal that the recently characterised RBPs LARP4A and LARP4B are differentially overexpressed in primary osteosarcoma and osteosarcoma lung metastases, as well as in prostate cancer. Depletion of LARP4A and LARP4B inhibited primary tumour growth and metastatic spread in xenograft studies, as well as inhibiting cell proliferation, motility and migration. Transcriptomic profiling combined with high content multiparametric cell cycle analysis unveiled a central role for LARP4B, but not LARP4A, in regulating cell cycle progression in osteosarcoma and prostate cancer cell lines, potentially through modulating the post-transcriptional regulation of RNA targets that include key cell cycle proteins such as Cyclins B1 and E2, Aurora B and E2F1. Our work assigns new functions to LARP4A and LARP4B as pro-tumorigenic proteins in bone and prostate cancer, highlights their similarities while indicating distinct functional aspects, and adds significantly to the rapidly increasing roles of RBPs in different cancer models. Uncovering clear biological roles for these paralogous proteins provides new avenues for identifying novel tissue-specific targets and potential druggable intervention.

cancer biology↗

bioRxiv2022

P2RX7 inhibition reduces breast cancer induced osteolytic lesions - implications for bone metastasis

Breast cancer metastasis to bone is a major contributor to morbidity and mortality in patients and remains an unmet clinical need. Purinergic signalling via the P2X7 receptor (P2RX7) in the primary tumour microenvironment is associated with progression of several cancers. It has also now become evident that intra-tumoural hypoxia facilitates cancer metastasis and reduces patient survival. In this study, we present data suggesting that hypoxia regulates the expression of P2RX7 in the primary tumour microenvironment; and importantly, inhibition with a selective antagonist (10mg/kg A740003) increased cancer cell death via apoptosis in a E0771/C57BL-6J syngeneic murine model. Furthermore, micro-computed tomography demonstrated reduced number of osteolytic lesions and lesion area following P2RX7 inhibition in absence of overt metastases by decreasing osteoclast numbers. We also demonstrate that activation of P2RX7 plays a role in the secretion of extracellular vesicles (EVs) from breast cancer cells. Mass-spectrometric analyses showed a distinct protein signature for EVs derived from hypoxic compared with normoxic cancer cells which elicit specific responses in bone cells that are associated with pre-metastatic niche formation. Thus, inhibiting P2RX7 provides a novel opportunity to preferentially target the hypoxic breast cancer cells preventing tumour progression and subsequent metastasis to bone

cancer biology↗

bioRxiv2021

The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties

Osteosarcoma (OS) is the most common type of primary bone cancer affecting children and adolescents. OS has a high propensity to spread, meaning the disease is often incurable and fatal. There have been no improvements in survival rates for decades. This highlights an urgent need for development of novel therapeutic strategies. In this study, we have produced in vitro and in vivo data that demonstrates the role of purinergic signalling, specifically, the B isoform of the purinergic receptor P2RX7 (herein termed " P2RX7B"), in OS progression and metastasis. Our data shows that P2RX7B expression confers a survival advantage in TE85+P2RX7B and MNNG-HOS+ P2RX7B human OS cell lines in vitro that is minimised following treatment with A740003, a specific P2RX7 antagonist. P2RX7B expression reduced cell adhesion and P2RX7B activation promoted invasion and migration in vitro, suggesting a probable metastatic phenotype. Using an in vivo OS xenograft model, MNNG-HOS+P2RX7B tumours exhibited ectopic bone formation that was abrogated with A740003 treatment. An increased metastatic phenotype was further demonstrated in vivo as expression of P2RX7B in primary tumour cells increased the propensity of the tumour to metastasise to the lungs. RNA-seq identified a novel gene axis, FN1/LOX/PDGFB/IGFBP3/BMP4, downregulated in response to A740003 treatment. In conclusion, our data indicates for the first time a role for P2RX7B in OS tumour growth, progression and metastasis. We show that P2RX7B is a potential therapeutic target in human OS. Novelty and ImpactWe provide evidence for the pro-tumorigenic role of the B isoform of the P2RX7 purinergic receptor in osteosarcoma (OS). In addition to increasing proliferation, P2RX7B increases the cancerous properties of OS cells, reducing adhesion and increasing migration and invasion. In vivo, P2RX7B does not affect primary tumour growth, but does lead to an increased propensity to metastasize. RNA-seq revealed a new axis of oncogenic genes inhibited by the P2RX7 antagonist and this data could potentially lead to new targets for OS treatment.

cancer biology↗

bioRxiv2019

Genome-wide association and functional analyses identify CASC20 and KIF26B as target loci in heterotopic ossification

Heterotopic ossification (HO) is bone formation that occurs after trauma within tissues that do not normally have the property of ossification, resulting in pain and disability. The genetic architecture of HO remains unclear. In the first genome-wide association studies of this disease, we identify the human-only long non-coding RNA-encoding gene CASC20 as a robust, replicating susceptibility locus for HO and KIF26B as a potential severity locus. We find that both CASC20 and KIF26B are expressed in human bone. Both CASC20 and KIF26B expression is upregulated upon BMP2 induced osteogenic differentiation in primary human mesenchymal stem cells, followed by RUNX2 and OSTERIX upregulation and mineralised nodule formation. A CRISPR-Cas9 mediated knockout of Kif26b inhibits BMP2-induced Runx2, Sp7/Osterix, Col1A1, Alp, and Bglap/Osteocalcin expression in a murine myocyte model of osteogenic trans-differentiation, and prevents mineralised nodule formation. These studies provide the first insights into the heritable biology of common, complex HO.

genetics↗