Benesch Matthew Gk, Wu Rongrong, Rog Colin J, Brindley David N, Ishikawa Takashi, Takabe Kazuaki
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, New York 14263, USA.
Department of Breast Surgery and Oncology, Tokyo Medical University Tokyo 160-8402, Japan.
Am J Cancer Res. 2024 Aug 25;14(8):4004-4027. doi: 10.62347/KQNW1871. eCollection 2024.
Lysophosphatidate (LPA)-mediated signaling is a vital component of physiological wound healing, but the pathway is subverted to mediate chronic inflammatory signaling in many pathologies, including cancers. LPA, as an extracellular signaling molecule, is produced by the enzyme autotaxin (ATX, gene name ) and signals through six LPA receptors (LPARs). Its signaling is terminated by turnover via the ecto-activity of three lipid phosphate phosphatases (LPPs, gene names ). Many pharmacological developments against the LPA-signaling axis are underway, primarily against ATX. An ATX inhibitor against pancreatic ductal adenocarcinoma (PDAC), a very aggressive disease with limited systemic therapeutic options, is currently in clinical trials, and represents the first in-class drug against LPA signaling in cancers. In the present study, we surveyed the expression of ATX, LPARs, and LPPs in human PDACs and their clinical outcomes in two large independent cohorts, the Cancer Genome Atlas (TCGA) and GSE21501. Correlation among gene expressions, biological function and the cell composition of the tumor microenvironment were analysed using gene set enrichment analysis and cell cyber-sorting with , and were significantly elevated in PDACs compared to normal pancreatic tissue, whereas , and where downregulated (all P≤0.003). Only demonstrated survival differences, with overall survival favoring -high patients (hazard ration 0.5-0.9). was also the only gene with enriched gene patterns for inflammatory and tissue repair gene sets. Epithelial (cancer) cells had increased and expression, and decreased , and gene expression (all P<0.02). Tumor fibroblasts had increased , and expression and decreased , and expression in both cohorts (all P≤0.01). Immune cell populations were not well correlated to gene expression in PDACs, but across both cohorts, cytolytic scores were increased in high-expressing , and tumors (P<0.01). Overall, in PDACs, may switch from an anti-to-pro tumor promoting gene with disease progression. and inhibition are also predicted to have potential therapeutic utility. Future multi-omics investigations are necessarily to validate which LPA signaling components are high-value candidates for pharmacological manipulation in PDAC treatment.
溶血磷脂酸（LPA）介导的信号传导是生理性伤口愈合的重要组成部分，但在包括癌症在内的许多病理过程中，该信号通路会被颠覆以介导慢性炎症信号传导。LPA作为一种细胞外信号分子，由自分泌运动因子（ATX，基因名称）酶产生，并通过六种LPA受体（LPARs）发出信号。其信号传导通过三种脂质磷酸磷酸酶（LPPs，基因名称）的胞外活性进行周转而终止。目前正在进行许多针对LPA信号轴的药物研发，主要是针对ATX。一种针对胰腺导管腺癌（PDAC）的ATX抑制剂目前正在进行临床试验，PDAC是一种侵袭性很强且全身治疗选择有限的疾病，该抑制剂代表了癌症中首个针对LPA信号传导的同类药物。在本研究中，我们在两个大型独立队列，即癌症基因组图谱（TCGA）和GSE21501中，调查了人类PDAC中ATX、LPARs和LPPs的表达及其临床结果。使用基因集富集分析和细胞网络分选分析基因表达、生物学功能与肿瘤微环境细胞组成之间的相关性，与正常胰腺组织相比，PDAC中 、 和 显著升高，而 、 和 下调（所有P≤0.003）。只有 显示出生存差异，高表达 的患者总生存期更长（风险比0.5 - 0.9）。 也是炎症和组织修复基因集基因模式富集的唯一基因。上皮（癌）细胞 、 表达增加， 、 基因表达降低（所有P<0.02）。在两个队列中，肿瘤成纤维细胞 、 表达增加， 、 表达降低（所有P≤0.01）。免疫细胞群体与PDAC中的基因表达相关性不佳，但在两个队列中，高表达 、 的肿瘤细胞溶解评分增加（P<0.01）。总体而言，在PDAC中， 可能会随着疾病进展从抗肿瘤促进基因转变为促肿瘤促进基因。 、 抑制也预计具有潜在治疗效用。未来的多组学研究有必要验证哪些LPA信号传导成分是PDAC治疗中药理学操作的高价值候选者。
