Dense stroma activates the TGF-β1/FBW7 axis to induce metabolic subtype switching in pancreatic cancer.

IF 10.1 2区医学 Q1 SURGERY International journal of surgery Pub Date : 2025-02-01 DOI:10.1097/JS9.0000000000002242

Zeyin Rong, Jianhui Yang, Jiang Liu, Qingcai Meng, Jie Hua, Zhen Tan, Bo Zhang, Yuan Liu, Qiong Du, Wei Wang, Xianjun Yu, Jin Xu, Chen Liang

{"title":"Dense stroma activates the TGF-β1/FBW7 axis to induce metabolic subtype switching in pancreatic cancer.","authors":"Zeyin Rong, Jianhui Yang, Jiang Liu, Qingcai Meng, Jie Hua, Zhen Tan, Bo Zhang, Yuan Liu, Qiong Du, Wei Wang, Xianjun Yu, Jin Xu, Chen Liang","doi":"10.1097/JS9.0000000000002242","DOIUrl":null,"url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease.Methods: Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes. The impact of transforming growth factor β (TGF-β)-1/F-box and WD repeat domain-containing 7 (FBW7) on the switch of the metabolic subtype was further validated in vitro and in vivo . Finally, cell growth was performed to identify the TGF-β1/FBW7 ratio as a molecular marker for gemcitabine resistance.Results: PDAC was stratified into the glycolytic subtype and lipogenic subtype. Furthermore, pancreatic cancer-associated fibroblasts-derived TGF-β1 and tumor cell-derived FBW7 were demonstrated to co-determine the metabolic phenotypes in PDAC. A high TGF-β1/FBW7 ratio always represented the glycolytic PDAC with dense stroma. This subtype of PDAC exhibited mesenchymal features and was predictive of unfavorable prognoses, despite being more sensitive than the lipogenic subtype to combination treatment with gemcitabine and an inhibitor of TGF-β receptor I (TGF-βR1).Conclusions: The TGF-β1/FBW7 ratio could be regarded as a molecular marker of metabolic phenotypes in PDAC and may contribute to the development of effective therapeutic strategies to improve the survival of PDAC patients.","PeriodicalId":14401,"journal":{"name":"International journal of surgery","volume":" ","pages":"1891-1903"},"PeriodicalIF":10.1000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International journal of surgery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/JS9.0000000000002242","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"SURGERY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Although several chemotherapy regimens have been developed over the past decades, few targeted therapies have shown a significant improvement in overall survival, partly due to the identification of PDAC as a single disease.

Methods: Combining metabolomic analysis and immunohistochemistry staining with Oil Red O staining, analysis for the oxygen consumption rate and extracellular acidification rate, we stratified pancreatic cancer cells into two subtypes. The impact of transforming growth factor β (TGF-β)-1/F-box and WD repeat domain-containing 7 (FBW7) on the switch of the metabolic subtype was further validated in vitro and in vivo . Finally, cell growth was performed to identify the TGF-β1/FBW7 ratio as a molecular marker for gemcitabine resistance.

Results: PDAC was stratified into the glycolytic subtype and lipogenic subtype. Furthermore, pancreatic cancer-associated fibroblasts-derived TGF-β1 and tumor cell-derived FBW7 were demonstrated to co-determine the metabolic phenotypes in PDAC. A high TGF-β1/FBW7 ratio always represented the glycolytic PDAC with dense stroma. This subtype of PDAC exhibited mesenchymal features and was predictive of unfavorable prognoses, despite being more sensitive than the lipogenic subtype to combination treatment with gemcitabine and an inhibitor of TGF-β receptor I (TGF-βR1).

Conclusions: The TGF-β1/FBW7 ratio could be regarded as a molecular marker of metabolic phenotypes in PDAC and may contribute to the development of effective therapeutic strategies to improve the survival of PDAC patients.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

致密基质激活TGF-β1/FBW7轴诱导胰腺癌代谢亚型转换。

背景：胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是最致命的疾病之一。尽管在过去的几十年中已经开发了几种化疗方案，但很少有靶向治疗显示出对总生存率的显着改善，部分原因是PDAC被确定为单一疾病。方法：结合代谢组学分析和免疫组化油红O染色、耗氧量和细胞外酸化率分析，将胰腺癌细胞分为两种亚型。在体外和体内进一步验证了转化生长因子β (TGF-β)-1/F-box和WD重复结构域7 （FBW7）对代谢亚型开关的影响。最后，通过细胞生长鉴定TGF-β1/FBW7比值作为吉西他滨耐药的分子标志物。结果：PDAC分为糖酵解型和脂肪生成型。此外，胰腺癌相关成纤维细胞衍生的TGF-β1和肿瘤细胞衍生的FBW7被证明共同决定PDAC的代谢表型。TGF-β1/FBW7比值较高，均代表糖酵解PDAC基质致密。该亚型PDAC表现出间充质特征，可预测不良预后，尽管其对吉西他滨和TGF-β受体I抑制剂（TGF-β r1）联合治疗更为敏感。结论：TGF-β1/FBW7比值可作为PDAC代谢表型的分子标志物，有助于制定有效的治疗策略，提高PDAC患者的生存率。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

International journal of surgery SURGERY-

CiteScore

17.70

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： The International Journal of Surgery (IJS) has a broad scope, encompassing all surgical specialties. Its primary objective is to facilitate the exchange of crucial ideas and lines of thought between and across these specialties.By doing so, the journal aims to counter the growing trend of increasing sub-specialization, which can result in "tunnel-vision" and the isolation of significant surgical advancements within specific specialties.