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ResearchIn-Press PreviewGastroenterology
Open Access | 10.1172/JCI163873
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
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Moniruzzaman, R.
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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
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Ji, B.
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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
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Liu, Y.
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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
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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
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Abbasgholizadeh, R.
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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
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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
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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
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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
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Tan, T.
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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
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Maitra, A.
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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
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Wang, H.
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Published May 4, 2023 - More info
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.