Rong Zeyin, Yang Jianhui, Liu Jiang, Meng Qingcai, Hua Jie, Tan Zhen, Zhang Bo, Liu Yuan, Du Qiong, Wang Wei, Yu Xianjun, Xu Jin, Liang Chen
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Int J Surg. 2025 Feb 1;111(2):1891-1903. doi: 10.1097/JS9.0000000000002242.
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.
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.
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).
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.
胰腺导管腺癌（PDAC）是致死率最高的疾病之一。尽管在过去几十年间已研发出多种化疗方案，但很少有靶向疗法能显著提高总生存率，部分原因是将PDAC视为单一疾病。
结合代谢组学分析、免疫组织化学染色与油红O染色、氧消耗率和细胞外酸化率分析，我们将胰腺癌细胞分为两种亚型。体外和体内进一步验证了转化生长因子β（TGF-β）-1/F盒和含WD重复结构域7（FBW7）对代谢亚型转换的影响。最后，进行细胞生长实验以确定TGF-β1/FBW7比值作为吉西他滨耐药的分子标志物。
PDAC被分为糖酵解亚型和脂肪生成亚型。此外，已证明胰腺癌相关成纤维细胞衍生的TGF-β1和肿瘤细胞衍生的FBW7共同决定了PDAC的代谢表型。高TGF-β1/FBW7比值始终代表具有致密基质的糖酵解型PDAC。这种亚型的PDAC表现出间充质特征，尽管比脂肪生成亚型对吉西他滨和转化生长因子β受体I（TGF-βR1）抑制剂联合治疗更敏感，但仍预示着不良预后。
TGF-β1/FBW7比值可被视为PDAC代谢表型的分子标志物，可能有助于制定有效的治疗策略以提高PDAC患者的生存率。
