多样化的空间谱学技术的发展，为了解癌症发病机制提供了前所未有的视角。在这里，我们首次进行了关于导管内乳头状黏液性肿瘤（IPMN）进展所伴随的空间转录组学和空间代谢组学变化的跨物种综合评估，IPMN是胰腺导管腺癌（PDAC）的真正囊性前体。我们用人类切除的IPMN组织（N= 23）以及IPMN小鼠突变Kras; Gnas模型的胰腺进行了基于基质辅助激光解析/电离（MALDI）质谱（MS）的空间成像和Visium空间转录组学（ST）（10X Genomics）分析。结论进一步与89例组织学确认为IPMN的患者囊性液体的脂质组分析，以及PDAC和正常组织的单细胞和批量转录组学数据进行了比较。IPMN组织的MALDI-MS分析揭示了长链羟基化硫酰胺，特别是C24：0（OH）和C24：1（OH）物种，在IPMN和PDAC肿瘤上皮中选择性富集。集成的ST分析证实，参与硫酸酯生物合成的配基转录本（包括UGT8，Gal3St1和FA2H）与硫酸酯富集区域共定位。囊性液体的脂质组分析确定了几种硫酸酯物种，包括C24：0（OH）和C24：1（OH）物种，在IPMN/PDAC患者中显著升高，与低级IPMN患者相比。通过选择性半乳糖脂合成酶抑制剂UGT8-IN-1去靶向硫酸酯代谢，造成细胞质内的致命噬菌体和随后的癌细胞死亡，这在体外实验中得到验证，并且减弱了突变Kras; Gnas异种移植瘤的肿瘤生长。UGT8和FA2H的转录水平也在PDAC转录组学数据集中显著富集，与非癌变区域相比，升高的肿瘤UGT8预示整体生存不良。增强的硫酸酯代谢是胰腺囊性前癌病变的早期代谢变化，并且在浸润性肿瘤中持续存在。靶向硫酸酯生物合成可能代表一种可操作的癌症干预漏洞。

The development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted the first integrated cross-species assessment of spatial transcriptomics and spatial metabolomics alterations associated with progression of intraductal papillary mucinous neoplasms (IPMN), bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).Matrix Assisted Laster Desorption/Ionization (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) (10X Genomics) was performed on human resected IPMN tissues (N= 23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN. Findings were further compared with lipidomic analyses of cystic fluid from 89 patients with histologically confirmed IPMNs, as well as single-cell and bulk transcriptomic data of PDAC and normal tissues.MALDI-MS analyses of IPMN tissues revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Integrated ST analyses confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1 , and FA2H , were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid identified several sulfatide species, including the C24:0(OH) and C24:1(OH) species, to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Targeting of sulfatide metabolism via the selective galactosylceramide synthase inhibitor, UGT8-IN-1, resulted in ceramide-induced lethal mitophagy and subsequent cancer cell death in vitro , and attenuated tumor growth of mutant Kras;Gnas allografts. Transcript levels of UGT8 and FA2H were also selectively enriched in PDAC transcriptomic datasets compared to non-cancerous areas, and elevated tumoral UGT8 was prognostic for poor overall survival.Enhanced sulfatide metabolism is an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception.