Faculty, Staff and Student Publications
Publication Date
6-15-2023
Journal
Journal of Clinical Investigation
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 mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (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 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.
Keywords
Mice, Animals, Proto-Oncogene Proteins p21(ras), Pancreatic Neoplasms, Protein Serine-Threonine Kinases, Carcinoma, Pancreatic Ductal, Carcinoma in Situ, Mice, Transgenic, Tumor Microenvironment, Mouse models, Protein kinases, Tumor suppressors, Gastroenterology
DOI
10.1172/JCI163873
PMID
37140994
PMCID
PMC10266776
PubMedCentral® Posted Date
6-15-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Digestive System Diseases Commons, Gastroenterology Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons