Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann...

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Bibliographic Details
Published in:Science advances 2023-02, Vol.9 (5), p.eadd6995-eadd6995
Main Authors: Sun, Chengcao, Ye, Youqiong, Tan, Zhi, Liu, Yuan, Li, Yajuan, Hu, Wei, Liang, Ke, Egranov, Sergey D, Huang, Lisa Angela, Zhang, Zhao, Zhang, Yaohua, Yao, Jun, Nguyen, Tina K, Zhao, Zilong, Wu, Andrew, Marks, Jeffrey R, Caudle, Abigail S, Sahin, Aysegul A, Gao, Jianjun, Gammon, Seth T, Piwnica-Worms, David, Hu, Jian, Chiao, Paul J, Yu, Dihua, Hung, Mien-Chie, Curran, Michael A, Calin, George A, Ying, Haoqiang, Han, Leng, Lin, Chunru, Yang, Liuqing
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Carcinoma, Pancreatic Ductal - metabolism
Cell Biology
Cell Line, Tumor
Cell Proliferation - genetics
Gene Expression Regulation, Neoplastic
Humans
Immunology
Kynurenine - genetics
Kynurenine - metabolism
Pancreatic Neoplasms
Pancreatic Neoplasms - pathology
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
SciAdv r-articles
Tumor Microenvironment - genetics
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Summary:One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 ( ) was triggered by the tumor cell-produced interleukin-6. Mechanistically, modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.add6995