The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration.

IF 11.4 1区 医学 Q1 ONCOLOGY
Chiara Cencioni, Silvia Malatesta, Virginia Vigiano Benedetti, Valerio Licursi, Livia Perfetto, Federica Conte, Danilo Ranieri, Armando Bartolazzi, Martina Kunkl, Loretta Tuosto, Alberto Larghi, Geny Piro, Antonio Agostini, Giampaolo Tortora, Vincenzo Corbo, Carmine Carbone, Francesco Spallotta
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引用次数: 0

Abstract

Background: Metabolic syndrome represents a pancreatic ductal adenocarcinoma (PDAC) risk factor. Metabolic alterations favor PDAC onset, which occurs early upon dysmetabolism. Pancreatic neoplastic lesions evolve within a dense desmoplastic stroma, consisting in abundant extracellular matrix settled by cancer associated fibroblasts (CAFs). Hereby, dysmetabolism and PDAC association was analyzed focusing on CAF functions.

Methods: PDAC development upon dysmetabolic conditions was investigated in: 1) high fat diet fed wild type immunocompetent syngeneic mice by orthotopic transplantation of pancreatic intraepithelial neoplasia (PanIN) organoids; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with/without an history of metabolic syndrome.

Results: The dysmetabolic-associated higher PDAC aggressiveness was paralleled by collagen fibril enrichment due to prolyl 4-hydroxylase subunit alpha 1 (P4HA1) increased function. Upon dysmetabolism, P4HA1 boosts collagen proline hydroxylation, intensifies collagen contraction strength, precluding PDAC infiltration. Noteworthy, semaglutide, an incretin agonist, prevents the higher dysmetabolism-dependent PDAC stromal deposition and allows T lymphocyte infiltration, reducing tumor development.

Conclusions: These results shed light on novel therapeutic options for PDAC patients with metabolic syndrome aimed at PDAC stroma reshape.

GLP-1R激动剂semaglutide重塑胰腺癌相关成纤维细胞,减少胶原脯氨酸羟基化,促进T淋巴细胞浸润。
背景:代谢综合征是胰腺导管腺癌(PDAC)的危险因素。代谢改变有利于PDAC的发病,它发生在代谢异常的早期。胰腺肿瘤病变在致密的间质中发展,由丰富的细胞外基质组成,由癌症相关的成纤维细胞(CAFs)沉淀。因此,以CAF功能为重点,分析代谢异常与PDAC的关联。方法:通过原位移植胰腺上皮内瘤变(PanIN)类器官,研究代谢异常条件下PDAC的发育情况:1)高脂饲料喂养野生型免疫活性同基因小鼠;2)从化疗naïve有/无代谢综合征史的PDAC患者中分离的原发性胰腺CAFs。结果:代谢障碍相关的PDAC侵袭性升高与脯氨酸4-羟化酶亚基α 1 (P4HA1)功能增加引起的胶原纤维富集相平行。在代谢异常时,P4HA1促进胶原脯氨酸羟基化,增强胶原收缩强度,阻止PDAC浸润。值得注意的是,司马鲁肽,一种肠促胰岛素激动剂,可以阻止代谢异常依赖性的PDAC间质沉积,并允许T淋巴细胞浸润,减少肿瘤的发展。结论:这些结果揭示了针对PDAC基质重塑的代谢综合征PDAC患者的新治疗选择。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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