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

Chengcao Sun; Youqiong Ye; Zhi Tan; Yuan Liu; Yajuan Li; Wei Hu; Ke Liang; Sergey D. Egranov; Lisa Angela Huang; Zhao Zhang; Yaohua Zhang; Jun Yao; Tina K. Nguyen; Zilong Zhao; Andrew Wu; Jeffrey R. Marks; Abigail S. Caudle; Aysegul A. Sahin; Jianjun Gao; Seth T. Gammon; David Piwnica-Worms; Jian Hu; Paul J. Chiao; Dihua Yu; Mien Chie Hung; Michael A. Curran; George A. Calin; Haoqiang Ying; Leng Han; Chunru Lin; Liuqing Yang

doi:10.1126/sciadv.add6995

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

Chengcao Sun, Youqiong Ye, Zhi Tan, Yuan Liu, Yajuan Li, Wei Hu, Ke Liang, Sergey D. Egranov, Lisa Angela Huang, Zhao Zhang, Yaohua Zhang, Jun Yao, Tina K. Nguyen, Zilong Zhao, Andrew Wu, Jeffrey R. Marks, Abigail S. Caudle, Aysegul A. Sahin, Jianjun Gao, Seth T. GammonDavid Piwnica-Worms, Jian Hu, Paul J. Chiao, Dihua Yu, Mien Chie Hung, Michael A. Curran, George A. Calin, Haoqiang Ying, Leng Han, Chunru Lin, Liuqing Yang

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Abstract

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 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 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 PVT1 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.

Original language	English (US)
Article number	eadd6995
Journal	Science Advances
Volume	9
Issue number	5
DOIs	https://doi.org/10.1126/sciadv.add6995
State	Published - Feb 2023

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Advanced Technology Genomics Core

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Sun, C., Ye, Y., Tan, Z., Liu, Y., Li, Y., Hu, W., Liang, K., Egranov, S. D., Huang, L. A., Zhang, Z., Zhang, Y., Yao, J., Nguyen, T. K., Zhao, Z., Wu, A., Marks, J. R., Caudle, A. S., Sahin, A. A., Gao, J., ... Yang, L. (2023). Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion. Science Advances, 9(5), Article eadd6995. https://doi.org/10.1126/sciadv.add6995

Sun, C, Ye, Y, Tan, Z, Liu, Y, Li, Y, Hu, W, Liang, K, Egranov, SD, Huang, LA, Zhang, Z, Zhang, Y, Yao, J, Nguyen, TK, Zhao, Z, Wu, A, Marks, JR, Caudle, AS , Sahin, AA , Gao, J , Gammon, ST , Piwnica-Worms, D , Hu, J , Chiao, PJ , Yu, D, Hung, MC, Curran, MA , Calin, GA , Ying, H, Han, L, Lin, C & Yang, L 2023, 'Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion', Science Advances, vol. 9, no. 5, eadd6995. https://doi.org/10.1126/sciadv.add6995

@article{1e9d23b262d44ba3937bcf722d2b7988,

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

abstract = "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 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 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 PVT1 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.",

author = "Chengcao Sun and Youqiong Ye and Zhi Tan and Yuan Liu and Yajuan Li and Wei Hu and Ke Liang and Egranov, {Sergey D.} and Huang, {Lisa Angela} and Zhao Zhang and Yaohua Zhang and Jun Yao and Nguyen, {Tina K.} and Zilong Zhao and Andrew Wu and Marks, {Jeffrey R.} and Caudle, {Abigail S.} and Sahin, {Aysegul A.} and Jianjun Gao and Gammon, {Seth T.} and David Piwnica-Worms and Jian Hu and Chiao, {Paul J.} and Dihua Yu and Hung, {Mien Chie} and Curran, {Michael A.} and Calin, {George A.} and Haoqiang Ying and Leng Han and Chunru Lin and Liuqing Yang",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors.",

year = "2023",

month = feb,

doi = "10.1126/sciadv.add6995",

language = "English (US)",

volume = "9",

journal = "Science Advances",

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T1 - Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion

AU - Sun, Chengcao

AU - Ye, Youqiong

AU - Tan, Zhi

AU - Liu, Yuan

AU - Li, Yajuan

AU - Hu, Wei

AU - Liang, Ke

AU - Egranov, Sergey D.

AU - Huang, Lisa Angela

AU - Zhang, Zhao

AU - Zhang, Yaohua

AU - Yao, Jun

AU - Nguyen, Tina K.

AU - Zhao, Zilong

AU - Wu, Andrew

AU - Marks, Jeffrey R.

AU - Caudle, Abigail S.

AU - Sahin, Aysegul A.

AU - Gao, Jianjun

AU - Gammon, Seth T.

AU - Piwnica-Worms, David

AU - Hu, Jian

AU - Chiao, Paul J.

AU - Yu, Dihua

AU - Hung, Mien Chie

AU - Curran, Michael A.

AU - Calin, George A.

AU - Ying, Haoqiang

AU - Han, Leng

AU - Lin, Chunru

AU - Yang, Liuqing

PY - 2023/2

Y1 - 2023/2

N2 - 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 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 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 PVT1 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.

AB - 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 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 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 PVT1 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.

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JO - Science Advances

JF - Science Advances

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M1 - eadd6995

ER -

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

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