不足的癌症治疗可能诱导衰老型癌细胞形成和耐药性。经诱导的衰老型癌（iSnCa）细胞的特征尚不清楚。胰腺导管腺癌（PDAC）对当前治疗的反应率低且持久性差。我们的研究旨在分析iSnCa细胞的性质以及细胞衰老与PDAC预后之间的关系。评估了吉西他滨诱导的衰老型癌细胞的特征，以及iSnCa细胞释放的衰老相关分泌表型（SASP）因子对周围PDAC细胞的影响。在接受吉西他滨基于新辅助化疗的PDAC患者中，调查了细胞衰老与预后之间的关系。接触到5 ng/mL吉西他滨可诱导PDAC细胞发生衰老，减少增殖并增加衰老相关β-半乳糖苷酶-细胞染色，而无细胞死亡；谷氨酸酶1（GLS1）和SASP因子的表达也增加，并导致周围PDAC细胞的上皮间质转变。通过GLS1抑制剂双-2-（5-苯乙酰胺基-1,2,4-噻二唑-2-基）乙基硫化物（BPTES）通过诱导凋亡选择性去除iSnCa细胞。在皮下肿瘤模型小鼠体内，通过不足的吉西他滨诱导PDAC细胞发生细胞衰老。 GLS1表达在接受吉西他滨基于新辅助化疗的PDAC患者中是一项独立的预后因素。这是首个确定PDAC中细胞衰老与GLS1之间关系的研究。观察到低剂量的吉西他滨诱导PDAC细胞发生衰老，并增加了GLS1表达。细胞衰老可能导致PDAC的治疗耐药性，因此针对iSnCa细胞中的GLS1可能有助于提高治疗效果。© 2023 UICC.

Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated β-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.© 2023 UICC.