Advertisement

ResearchIn-Press PreviewGastroenterology Open Access | 10.1172/JCI163873

Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia

Hua Wang,1 Rohan Moniruzzaman,2 Lei Li,2 Baoan Ji,3 Yi Liu,1 Xiangsheng Zuo,1 Reza Abbasgholizadeh,2 Jun Zhao,2 Guangchao Liu,2 Ruiqi Wang,2 Hongli Tang,4 Ryan Sun,5 Xiaoping Su,6 Tse-Hua Tan,7 Anirban Maitra,8 and Huamin Wang2

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Wang, H. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Moniruzzaman, R. in: JCI | PubMed | Google Scholar |

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Li, L. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Ji, B. in: JCI | PubMed | Google Scholar |

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar |

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Zuo, X. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Abbasgholizadeh, R. in: JCI | PubMed | Google Scholar |

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Zhao, J. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Liu, G. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Wang, R. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Tang, H. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Sun, R. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Su, X. in: JCI | PubMed | Google Scholar

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Tan, T. in: JCI | PubMed | Google Scholar |

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Maitra, A. in: JCI | PubMed | Google Scholar |

1Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

2Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

3Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, United States of America

4The Advanced Technology Genomics Core, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

5Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

6Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

7Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan

8The University of Texas M.D. Anderson Cancer Center, Houston, United States of America

Find articles by Wang, H. in: JCI | PubMed | Google Scholar |

Published May 4, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI163873.
Copyright © 2023, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 4, 2023 - Version history
View PDF
Abstract

Ras plays an essential role in the development of acinar to ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The switching mechanisms from low Ras activity to high Ras activity that is required for development and progression of pancreatic intraepithelial neoplasia (PanIN) are unclear. In this study, we found that HPK1 was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase activating protein (RasGAP) and upregulated RasGAP activity. Using the transgenic mouse models of HPK1 or M46, a kinase-dead mutant of HPK1, we showed that HPK1 inhibited Ras activity and its downstream signaling and regulated acinar cell plasticity. M46 promoted the development of ADM and PanINs. Expression of M46 in KrasG12D;Bac mice promoted the infiltration of myeloid-derived suppressor cells and macrophages, inhibited the infiltration of T cells, and accelerated the progression of PanINs to invasive and metastatic PDAC, while HPK1 attenuated mutant Kras-driven PanIN progression. Our results showed that HPK1 plays an important role in ADM and the progression of PanINs by regulating Ras signaling. Loss of HPK1 kinase activity promotes an immunosuppressive tumor microenvironment and accelerates the progression of PanINs to PDAC.

Graphical Abstract
graphical abstract
Supplemental material

View

Version history
  • Version 1 (May 4, 2023): In-Press Preview
Advertisement
Advertisement