PDF(Pubmed)
Abstract：
Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.
摘要：
新辅助化疗可以改善患有交界性和不可切除的胰腺导管腺癌的患者的生存率；然而，对化疗的异质性反应仍然是一个重大的临床挑战。这里,我们对未经化疗和化疗后(CTX后)切除的患者样本(放化疗除外)进行了RNA测序(n=97)和多重免疫荧光(n=122),以确定新辅助化疗的影响.转录组分析结合高分辨率映射的全组织切片鉴定GATA6（经典），KRT17(基底样)和细胞色素P4503A(CYP3A)共表达细胞,其在CTX切除后的样品中优先富集。CTX后GATA6hi和KRT17hi细胞的持续存在与mFOLFIRINOX（mFFX）后的不良生存率显着相关，但不是吉西他滨（GEM），治疗。对来自化疗初始和CTX后样本的类器官模型的分析表明，CYP3A表达是化疗反应的预测因子，表达CYP3A的药物解毒途径可以代谢前药伊立替康，mFFX的组成部分。这些发现确定了残留疾病中表达CYP3A的药物耐受性细胞表型，这可能最终为辅助治疗选择提供信息。
