Spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment

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. 14 specimens received no treatment prior to resection; 7 specimens received neoadjuvant chemotherapy, radiotherapy, losartan, and/or nivolumab prior to resection

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是一种致死性极强且治疗耐受的恶性肿瘤。目前胰腺癌的分子分型仍处于初级阶段，尚未能为临床诊疗或药物研发提供指导。
本研究针对43例经新辅助治疗或初治的原发性胰腺导管腺癌肿瘤标本，采用单细胞核RNA测序（single-nucleus RNA-seq）与全转录组数字空间分析（SP），构建了胰腺癌多细胞亚型与空间群落的高分辨率分子图谱。
本研究在恶性细胞与成纤维细胞中鉴定出多种基因表达程序，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，本研究揭示了三类多细胞群落：经典型、鳞状样-基底样型与治疗富集型。
本研究建立的精细化分子与细胞分类系统，可通过临床试验分层以及为特定细胞表型与多细胞相互作用的治疗靶点开发提供研究路线图，推动胰腺癌精准肿瘤学的发展。
本研究纳入的43例标本中，14例在切除术术前未接受任何治疗；7例在切除术术前接受了新辅助化疗、放疗、氯沙坦及/或纳武利尤单抗治疗。