Disruption of LPA‐LPAR1 pathway results in lung tumor growth inhibition by downregulating B7‐H3 expression in fibroblasts

Abstract

BackgroundLysophosphatidic acids (LPAs) belong to a class of bioactive lysophospholipids with multiple functions including immunomodulatory roles in tumor microenvironment (TME). LPA exerts its biological effects via its receptors that are highly expressed in fibroblasts among other cell types. As cancer‐associated fibroblasts (CAFs) are a key component of the TME, it is important to understand LPA signaling and regulation of receptors in fibroblasts or CAFs and associated regulatory roles on immunomodulation‐related molecules.MethodsCluster analysis, immunoblotting, real‐time quantitative‐PCR, CRISPR‐Cas9 gene editing system, immunohistochemical staining, coculture model, and in vivo xenograft model were used to investigate the effects of LPA‐LPAR1 on B7‐H3 in tumor promotion of CAFs.ResultsIn this study, we found that LPAR1 and CD276 (B7‐H3) were generally highly expressed in fibroblasts with good expression correlation. LPA induced B7‐H3 up‐expression through LPAR1, and stimulated fibroblasts proliferation that could be inhibited by silencing LPAR1 or B7‐H3 as well as small molecule LPAR1 antagonist (Ki16425). Using engineered fibroblasts and non‐small cell lung carcinoma (NSCLC) cell lines, subsequent investigations demonstrated that CAFs promoted the proliferation of NSCLC in vitro and in vivo, and such effect could be inhibited by knocking out LPAR1 or B7‐H3.ConclusionThe present study provided new insights for roles of LPA in CAFs, which could lead to the development of innovative therapies targeting CAFs in the TME. It is also reasonable to postulate a combinatory approach to treat malignant fibrous tumors (such as NSCLC) with LPAR1 antagonists and B7‐H3 targeting therapies.

Combination of nucleic acid amplification and CRISPR/Cas technology in pathogen detection

“…Meanwhile, the application of CRISPR/Cas system also provides new ideas and methods for the optimization and improvement of PCR technology. In order to overcome the shortcomings of PCR, researchers have explored new molecular detection techniques by combining PCR technology with CRISPR/Cas technology, and through further improvement and optimization, the technology has been widely used in many fields and has had a great impact ( Rakshit et al, 2022 ; Zhang et al, 2022 ; Cao et al, 2023 ; Meng et al, 2023 ; Tian et al, 2023 ).…”

“…(A) Schematic illustration of the Carms assay for distinguishing Salmonella enterica species with single-nucleotide resolution and the investigation of the resistance of drug-resistant S. enterica to salt stress (Yang et al, 2022); (B) proposed CCB-Detection for Staphylococcus aureus sensing (Zhou et al, 2020(Zhou et al, ). 10.3389/fmicb.2024 Frontiers in Microbiology 04 frontiersin.org been widely used in many fields and has had a great impact (Rakshit et al, 2022;Cao et al, 2023;Meng et al, 2023;Tian et al, 2023).…”