Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease with limited treatment options and poor survival. We studied 73 samples from 21 patients (7 treatment-naive and 14 treated with neoadjuvant regimens), analyzing distinct spatial units and performing bulk proteogenomics, single cell sequencing, and cellular imaging. Spatial drivers, including mutant KRAS, SMAD4, and GNAQ, were associated with differential phosphosignaling and metabolic responses compared to wild type. Single cell subtyping discovered 12 of 21 tumors with mixed basal and classical features. Trefoil factor family members were upregulated in classical populations, while the basal populations showed enhanced expression of mesenchymal genes, including VIM and IGTB1. Acinar-ductal metaplasia (ADM) populations, present in 95% of patients, with 46% reduction of driver mutation fractions compared to tumor populations, exhibited suppressive and oncogenic features linked to morphologic states. We identified coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin receptor expression in tumor cells. Higher expression of angiogenic and stress response genes in dendritic cells compared to tumor cells suggests they have a pro-tumorigenic role in remodeling the microenvironment. Treated samples contain a three-fold enrichment of inflammatory CAFs when compared to untreated samples, while other CAF subtypes remain similar. A subset of tumor and/or ADM-specific biomarkers showed differential expression between treatment groups, and several known drug targets displayed potential cross-cell type reactivities. This resolution that spatially defined single cell omics provides reveals the diversity of tumor and microenvironment populations in PDAC. Such understanding may lead to more optimal treatment regimens for patients with this devastating disease.

中文翻译：

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在未经治疗和耐药的胰腺癌中，空间驱动因素和癌症前期人群与微环境合作

胰腺导管腺癌（PDAC）是一种致命疾病，治疗选择有限且生存期较差。我们研究了21例患者的73份样本（7例未接受过治疗，14例接受了新辅助治疗），分析了不同的空间单位并进行了大规模蛋白质组学，单细胞测序和细胞成像。与野生型相比，包括突变型KRAS，SMAD4和GNAQ在内的空间驱动因子与差异磷信号和代谢反应有关。单细胞亚型分析发现了21种具有混合基础和经典特征的肿瘤。三叶因子家族成员在经典种群中上调，而基础种群显示间充质基因（包括VIM和IGTB1）的表达增强。在95％的患者中存在腺泡导管化生（ADM）人群，与肿瘤群体相比，具有高达46％的驱动子突变率降低，表现出与形态学状态相关的抑制和致癌特征。我们确定了疲惫和调节性T细胞中TIGIT的协调表达以及肿瘤细胞中Nectin受体的表达。与肿瘤细胞相比，树突状细胞中血管生成和应激反应基因的表达更高，表明它们在微环境重构中具有促肿瘤作用。与未处理的样品相比，处理过的样品含有三倍的炎性CAF富集，而其他CAF亚型保持相似。肿瘤和/或ADM特异性生物标志物的子集显示治疗组之间的差异表达，几种已知的药物靶标显示出潜在的跨细胞类型反应性。空间定义的单细胞组学提供的这种分辨率揭示了PDAC中肿瘤和微环境种群的多样性。这种理解可以为患有这种毁灭性疾病的患者带来更理想的治疗方案。