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Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma

Oncogene volume 36, pages 1232–1244 (2017)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high degree of inflammation and profound immune suppression. Here we identify Yes-associated protein (Yap) as a critical regulator of the immunosuppressive microenvironment in both mouse and human PDAC. Within Kras:p53 mutant pancreatic ductal cells, Yap drives the expression and secretion of multiple cytokines/chemokines, which in turn promote the differentiation and accumulation of myeloid-derived suppressor cells (MDSCs) both in vitro and in vivo. Pancreas-specific knockout of Yap or antibody-mediated depletion of MDSCs promoted macrophage reprogramming, reactivation of T cells, apoptosis of Kras mutant neoplastic ductal cells and pancreatic regeneration after acute pancreatitis. In primary human PDAC, YAP expression levels strongly correlate with an MDSC gene signature, and high expression of YAP or MDSC-related genes predicts decreased survival in PDAC patients. These results reveal multifaceted roles of YAP in PDAC pathogenesis and underscore its promise as a therapeutic target for this deadly disease.

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Acknowledgements

We thank Drs T Jacks (MIT), DJ Pan (Johns Hopkins) and CV Wright (Vanderbilt) for producing and sharing the original mouse strains used in this study. We are grateful for the helpful suggestions and critical comments of our manuscript from Dr S Ostrand-Rosenberg (UMBC). We would also like to thank Dr Karen Creswell from the Flow Cytometry and Cell Sorting Shared Resource (FCSR) for her technical guidance. We appreciate the technical assistance from FCSR, Microscopy & Imaging Shared Resource (MISR), Histopathology & Tissue Shared Resource (HTSR) and Genomics & Epigenomics Shared Resource (GESR) at Lombardi Cancer Center Shared Resources. We thank the husbandry staff and technicians of the Division of Comparative Medicine (DCM) at Georgetown University for support in our animal studies. CY is supported by NIH (R01CA187090), the V Foundation and the Advocure foundation. LMW is the PI of NIH (R01CA50633), and Cancer Center Support Grant (CA051008) that also supports the Lombardi Cancer Center Shared Resources.

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  1. S Murakami, D Shahbazian, R Surana and W Zhang: These authors contributed equally to this work.

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  1. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    S Murakami, D Shahbazian, R Surana, W Zhang, H Chen, G T Graham, S M White, L M Weiner & C Yi

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  1. S Murakami
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Murakami, S., Shahbazian, D., Surana, R. et al. Yes-associated protein mediates immune reprogramming in pancreatic ductal adenocarcinoma. Oncogene 36, 1232–1244 (2017). https://doi.org/10.1038/onc.2016.288

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