Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
Section Surgical Research, University Clinic Heidelberg, Heidelberg, Germany.
Nat Cancer. 2023 Sep;4(9):1362-1381. doi: 10.1038/s43018-023-00628-6. Epub 2023 Sep 7.
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 GATA6 and KRT17 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.
新辅助化疗可以提高交界性和不可切除的胰腺导管腺癌患者的生存率；然而，对化疗的异质反应仍然是一个重大的临床挑战。在这里，我们对化疗前和化疗后（CTX 后）切除的患者样本（排除放化疗）进行了 RNA 测序（n=97）和多重免疫荧光（n=122），以定义新辅助化疗的影响。转录组分析结合全组织切片的高分辨率图谱鉴定了 GATA6（经典）、KRT17（基底样）和细胞色素 P4503A（CYP3A）共表达细胞，这些细胞在 CTX 后切除的样本中优先富集。CTX 后 GATA6 和 KRT17 细胞的持续存在与 mFOLFIRINOX（mFFX）治疗后生存不良显著相关，但与吉西他滨（GEM）治疗无关。对来自化疗前和 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，并且 CYP3A 表达的药物解毒途径可以代谢 mFFX 的前药伊立替康。这些发现确定了残留疾病中具有耐药性的 CYP3A 表达药物耐受细胞表型，这最终可能为辅助治疗选择提供信息。
