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Sci Rep. 2019 Dec 3;9(1):18257. doi: 10.1038/s41598-019-54791-x.

Computational STAT3 activity inference reveals its roles in the pancreatic tumor microenvironment.

Author information

1
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA.
2
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA. chao.cheng@bcm.edu.
3
Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. chao.cheng@bcm.edu.
4
The Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA. chao.cheng@bcm.edu.

Abstract

Transcription factor (TF) STAT3 contributes to pancreatic cancer progression through its regulatory roles in both tumor cells and the tumor microenvironment (TME). In this study, we performed a systematic analysis of all TFs in patient-derived gene expression datasets and confirmed STAT3 as a critical regulator in the pancreatic TME. Importantly, we developed a novel framework that is based on TF target gene expression to distinguish between environmental- and tumor-specific STAT3 activities in gene expression studies. Using this framework, our results novelly showed that compartment-specific STAT3 activities, but not STAT3 mRNA, have prognostications towards clinical values within pancreatic cancer datasets. In addition, high TME-derived STAT3 activity correlates with an immunosuppressive TME in pancreatic cancer, characterized by CD4 T cell and monocyte infiltration and high copy number variation burden. Where environmental-STAT3 seemed to play a dominant role at primary pancreatic sites, tumor-specific STAT3 seemed dominant at metastatic sites where its high activity persisted. In conclusion, by combining compartment-specific inference with other tumor characteristics, including copy number variation and immune-related gene expression, we demonstrate our method's utility as a tool to generate novel hypotheses about TFs in tumor biology.

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