mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote Kras G12D -Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis.

Autor:	Zhao Y; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Schoeps B; Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Yao D; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Zhang Z; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Schuck K; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Tissen V; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Jäger C; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Schlitter AM; Institute of Pathology, Technical University of Munich, Munich, Germany., van der Kammen R; Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Ludwig C; Bavarian Center for Biomolecular Mass Spectrometry, Technical University of Munich, Freising, Germany., D'Haese JG; Department of General, Visceral, and Transplantation, Ludwig Maximilians University, Munich, Germany., Raulefs S; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Maeritz N; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Shen S; Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China., Zou X; Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China., Krüger A; Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Kleeff J; Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Germany., Michalski CW; Department of General Surgery, University of Ulm, Ulm, Germany., Friess H; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany., Innocenti M; Heidelberg University Biochemistry Center, Heidelberg University, Heidelberg, Germany., Kong B; Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; German Cancer Consortium at the partner site Munich, Munich, Germany. Electronic address: bo.kong@tum.de.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2021 Apr; Vol. 160 (5), pp. 1755-1770.e17. Date of Electronic Publication: 2021 Jan 01.
DOI:	10.1053/j.gastro.2020.12.061
Abstrakt:	Background & Aims: Oncogenic Kras G12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of Kras G12D , thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. Methods: A mouse model of inflammation-accelerated Kras G12D -driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. Results: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote Kras G12D -driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents Kras G12D -driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. Conclusions: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation. (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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