Refined molecular taxonomy and treatment remodeling of pancreatic cancer using single-cell resolution

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and treatment-refractory cancer. Molecular stratification in pancreatic cancer remains rudimentary and does not yet inform clinical management or therapeutic development. Here we construct a high-resolution molecular landscape of the multicellular subtypes and spatial communities that compose PAC using single-nucleus RNA-seq and whole-transcriptome digital spatial profiling (SP) of 43 primary PDAC tumor specimens that either received neoadjuvant therapy or were treatment-naïve. We uncovered expression programs across malignant cells and fibroblasts, including a newly-identified neural-like progenitor malignant cell program that was enriched after chemotherapy and radiotherapy and associated with poor prognosis in independent cohorts. Integrating spatial and cellular profiles revealed three multicellular communities: classical, squamoid-basaloid, and treatment-enriched. Our refined molecular and cellular taxonomy can advance precision oncology in PAC through stratification in clinical trials and as roadmap for therapeutic targeting of specific cellular phenotypes and multicellular interactions. 18 specimens received no treatment prior to resection; 25 specimens received neoadjuvant chemoradiation therapy (e.g. CRT = FOLFIRINOX), losartan (L), and/or nivolumab (N) prior to resection; 2 specimens were non-malignant

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是一种致死率极高且治疗抵抗性极强的癌症。目前胰腺癌的分子分层仍不完善，尚未能为临床管理或治疗药物研发提供指导。本研究对43例原发性PDAC肿瘤标本进行了研究，其中部分接受过新辅助治疗，其余为初治未接受治疗者；通过单细胞核RNA测序（single-nucleus RNA-seq）与全转录组数字空间分析（SP），构建了构成胰腺癌的多细胞亚型与空间群落的高分辨率分子图谱。研究揭示了恶性细胞与成纤维细胞中的多种表达程序，其中包括新发现的神经样祖细胞恶性细胞表达程序：该程序在放化疗后出现富集，且在独立队列中与不良预后显著相关。整合空间特征与细胞特征后，本研究识别出三类多细胞群落：经典型、鳞样-基底样型与治疗富集型。本研究优化的分子与细胞分类系统，可通过临床试验中的患者分层，以及为特定细胞表型与多细胞相互作用的治疗靶向提供研究路线图，从而推动胰腺癌的精准肿瘤学发展。本研究纳入的43例标本中，18例在手术切除前未接受任何治疗；25例在手术切除前接受了新辅助放化疗（如FOLFIRINOX方案化疗）、氯沙坦（L）以及/或纳武利尤单抗（N）治疗；另有2例为非恶性标本。