PLXDC1+ Tumor-Associated Pancreatic Stellate Cells Promote Desmoplastic and Immunosuppressive Niche in Pancreatic Ductal Adenocarcinoma

被引：0

作者：

Du, Yanhua ^{[1
,2
]}

Zhao, Yizhou ^{[1
]}

Li, Judong ^{[3
]}

Wang, Jiaxin ^{[1
]}

You, Shenglan ^{[1
]}

Zhang, Yao ^{[1
]}

Zhang, Li ^{[1
,2
]}

Yang, Jihong ^{[4
]}

Alinejad-Rokny, Hamid ^{[5
]}

Cheng, Shujie ^{[4
]}

Shao, Chenghao ^{[3
]}

Zou, Duowu ^{[1
]}

Ye, Youqiong ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Ctr Immune Related Dis,Shanghai Inst Immunol,Dept, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Yale Inst Immune Metab, State Key Lab Syst Med Canc, Sch Med, Shanghai 20025, Peoples R China

[3] Naval Med Univ, Changzheng Hosp, Dept Pancreat Biliary Surg, Shanghai 200003, Peoples R China

[4] Hebei Univ, Affiliated Hosp, Dept Hepatobiliary Surg, Hebei Key Lab Gen Surg Digital Med, Baoding 071000, Peoples R China

[5] UNSW Sydney, Sch Biomed Engn, UNSW BioMed Machine Learning Lab BML, Sydney, NSW 2052, Australia

来源：

ADVANCED SCIENCE | 2025年 / 12卷 / 18期

基金：

上海市自然科学基金; 中国国家自然科学基金;

关键词：

activation; heterogeneity; immunotherapy resistance; pancreatic stellate cells (PSCs); PLXDC1(+) tumor-associated PSCs; single-cell and spatial transcriptomes; SINGLE-CELL; CANCER; MICROENVIRONMENT; FIBROBLASTS; MODELS;

D O I：

10.1002/advs.202415756

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Pancreatic stellate cells (PSCs) contribute to pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance, yet their detailed functions remain unclear. This study combined RNA sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on sorted PSCs from adjacent normal and PDAC tissues to investigate their transcriptional and epigenetic activation. PSCs heterogeneity and functions are characterized through bulk, single-cell, and spatial transcriptomes, as well as in situ sequencing. The clinical relevance of PSCs in immunotherapy is assessed using an in-house immune-checkpoint blockade (ICB) treatment cohort. Findings showed that stress and hypoxia signaling activated PSCs in PDAC. Three common PSCs (CPSCs) and four tumor-associated PSCs (TPSCs) are identified, each with distinct functions. CPSCs differentiated into CCL19+ TPSCs in immune-enriched regions, MYH11+ TPSCs in the stromal region, and PLXDC1+ TPSCs, which exhibited cancer-associated myofibroblasts (myCAFs) phenotype linked to poor prognosis. Notably, PLXDC1+ TPSCs, located near aggressive LRRC15+ myCAFs and SPP1+ macrophages, formed a desmoplastic and immunosuppressive niche around the tumor boundary, promoting CD8 T cell exhaustion. Single-cell transcriptomics of PDAC patients treated with ICB revealed that PLXDC1+ TPSCs correlated with poor immunotherapy efficacy. Overall, this study provides key insights into PSCs in PDAC and potential therapeutic targets.

引用

页数：17

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