The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties

Abstract

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.

P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization

“…Among them, P2X7B and nfP2X7 isoforms have attracted most attention due to their inabilities to form macropore followed by cell death (22,69). The preferential expression of P2RX7B variant has also been observed in OS, which regulates OS growth and metastasis (33). Moreover, eATP induces nfP2RX7 expression and thus enhances tumor cell survival (22).…”

“…With regard to OS, various studies have also been conducted on the role of glucose metabolism in tumor progression and underlying mechanisms (30)(31)(32). Previous studies have suggested that P2RX7 is involved in biological behavior of OS cells (33,34). However, to our knowledge, whether and how P2RX7 regulates OS growth and metastasis through metabolic reprogramming remains unclear.…”

A2A Receptor contributes to tumor progression in P2X7 null mice

“…Following dehydration, sections were mounted with EUKITT (Kindler GmbH), and images acquired thanks to NIS-elements software with a Nikon Eclipse 90i digital microscope (Nikon Instruments, Europe). The percentage of positive cells was quantified using the QuPath free software for immunohistochemical analysis (Bankhead et al, 2017) as previously described (Tattersall et al, 2021).…”

C‐terminal variants of the P2X7 receptor are associated with prostate cancer progression and bone metastasis – evidence from clinical and pre‐clinical data

“…This naturally occurring P2X7RB isoform maintains ATP-stimulated channel activity but not pore permeabilization [2, 3]. P2X7RB is upregulated in epithelial cancer cells [3] and associated with the trophic activity of primary bone cancer [2,4,5]. These findings have highlighted the importance of defining the role of P2X7R C-terminal truncated variants in cancer progression, particularly considering that data on…”