Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2025
Evolution of the Spatial transcriptomic landscape during the progression of high-grade pancreatic intraductal papillary mucinous neoplasms to invasive cancer.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Peng Sirui, Chen Qiangxing, Chen Zixin, Yao Mengling, Cai Yunqiang, He Du, Cai Yu, Cheng Ke, Li Jun, Cai He, Gao Pan, Gu Xiafei, Wang Xin, Li Yongbin, Zhang Man, Meng Lingwei, Xia Qi, Xu Panpan, Dan Xie, Zhou Jin, Wu Zhong, Peng Bing
Аннотация
BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are known precancerous lesions whose malignant transformation to pancreatic ductal adenocarcinoma (PDAC) worsens prognosis. Current experimental models inadequately elucidate the molecular mechanisms driving this progression.
METHODS: We performed spatial transcriptomics (ST) on three fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC. We used Spatial inferCNV to profile the evolutionary clone trajectory. We utilize SpaCET to identify the tumor region and adjacent tumor microenvironment (TME) feature variation, as well as its crosstalk between tumor cells by CellChat.
RESULTS: Our findings identified the master transcript factors and critical signaling pathways that might be involved in the progression of IPMN to invasive PDAC. Moreover, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. We identified a significant heterogeneity among PDAC tissue with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. Compared to IPMN, PDAC showed immune landscape remodeling: CD4+ T cells and dendritic cells depleted, while immunosuppressive M2 macrophages increased. In addition, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC.
CONCLUSIONS: Our study integrates multiple computational approaches for spatial transcriptomics to identify ELF3/MYC/KLF4 amplifications during IPMN-to-PDAC progression, as well as 7 heterogeneous subclones with functions including hypoxia and EMT, alongside immune-stromal landscape remodeling and tumor-adjacent myofibroblastic CAF enrichment.
METHODS: We performed spatial transcriptomics (ST) on three fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC. We used Spatial inferCNV to profile the evolutionary clone trajectory. We utilize SpaCET to identify the tumor region and adjacent tumor microenvironment (TME) feature variation, as well as its crosstalk between tumor cells by CellChat.
RESULTS: Our findings identified the master transcript factors and critical signaling pathways that might be involved in the progression of IPMN to invasive PDAC. Moreover, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. We identified a significant heterogeneity among PDAC tissue with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. Compared to IPMN, PDAC showed immune landscape remodeling: CD4+ T cells and dendritic cells depleted, while immunosuppressive M2 macrophages increased. In addition, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC.
CONCLUSIONS: Our study integrates multiple computational approaches for spatial transcriptomics to identify ELF3/MYC/KLF4 amplifications during IPMN-to-PDAC progression, as well as 7 heterogeneous subclones with functions including hypoxia and EMT, alongside immune-stromal landscape remodeling and tumor-adjacent myofibroblastic CAF enrichment.