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

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