Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways

Juin, A., Spence, H. J. and Machesky, L. M. (2024) Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways. Journal of Pathology, (doi: 10.1002/path.6248) (PMID:38229581) (Early Online Publication)

Abstract

MAP4K4 is a serine/threonine kinase of the STE20 family involved in the regulation of actin cytoskeleton dynamics and cell motility. It has been proposed as a target of angiogenesis and inhibitors show potential in cardioprotection. MAP4K4 also mediates cell invasion in vitro, is overexpressed in various types of cancer, and is associated with poor patient prognosis. Recently, MAP4K4 has been shown to be overexpressed in pancreatic cancer, but its role in tumour initiation, progression, and metastasis is unknown. Here, using the Kras G12D Trp53 R172H Pdx1‐Cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC), we show that deletion of Map4k4 drives tumour initiation and progression. Moreover, we report that the acceleration of tumour onset is also associated with an overactivation of ERK and AKT, two major downstream effectors of KRAS, in vitro and in vivo. In contrast to the accelerated tumour onset caused by loss of MAP4K4, we observed a reduction in metastatic burden with both the KPC model and in an intraperitoneal transplant assay indicating a major role of MAP4K4 in metastatic seeding. In summary, our study sheds light on the dichotomous role of MAP4K4 in the initiation of PDAC onset, progression, and metastatic dissemination. It also identifies MAP4K4 as a possible druggable target against pancreatic cancer spread, but with the caveat that targeting MAP4K4 might accelerate early tumorigenesis. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

• Item Type: Articles
• Additional Information: LMM was funded by Cancer Research UK core grants to the Beatson Institute (A17196,A31287, and A24452).
• Status: Early Online Publication
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Machesky, Professor Laura and Juin, Dr Amelie and Spence, Dr Heather

Creator Roles

Juin, A.: Conceptualization, Data curation, Writing – original draft
Machesky, L.: Conceptualization, Writing – original draft
Spence, H.: Data curation

• Authors: Juin, A., Spence, H. J., and Machesky, L. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Pathology
• Publisher: Wiley
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 17 January 2024
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Journal of Pathology 2024
• Publisher Policy: Reproduced under a Creative Commons licence