Integrated spatial transcriptomics and lipidomics of precursor lesions of pancreatic cancer identifies enrichment of long chain sulfatide biosynthesis as an early metabolic alteration

作者：Marta Sans, Yihui Chen, Fredrik I. Thege, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, Jianjun Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal Rajapakshe, Mark W. Hurd, Ricardo A. Léon-Letelier, Jody V. Vykoukal, Jennifer B. Dennison, Kim‐Anh Do, Robert A. Wolff, Paola A. Guerrero, Michael P. Kim, C. Max Schmidt, Anirban Maitra, Samir Hanash, Johannes F. Fahrmann · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.08.14.553002 · 被引用次数：7 · 研究领域：Pancreatic and Hepatic Oncology Research、Single-cell and spatial transcriptomics、Epigenetics and DNA Methylation

Abstract Background 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). Methods 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. Results 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 I...