mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis

Zhao, Yamin; Schoeps, Benjamin; Yao, Dianbo; Zhang, Zhiheng; Schuck, Kathleen; Tissen, Vivien; Jäger, Carsten; Schlitter, Anna Melissa; van der Kammen, Rob; Ludwig, Christina; D’Haese, Jan G.; Raulefs, Susanne; Maeritz, Nadja; Shen, Shanshan; Zou, Xiaoping; Krüger, Achim; Kleeff, Jörg; Michalski, Christoph W.; Friess, Helmut; Innocenti, Metello; Kong, Bo

doi:10.1053/j.gastro.2020.12.061

2021

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Titel:: mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis
Dokumenttyp:: Zeitschriftenaufsatz
Autor(en):: Zhao, Yamin; Schoeps, Benjamin; Yao, Dianbo; Zhang, Zhiheng; Schuck, Kathleen; Tissen, Vivien; Jäger, Carsten; Schlitter, Anna Melissa; van der Kammen, Rob; Ludwig, Christina; D’Haese, Jan G.; Raulefs, Susanne; Maeritz, Nadja; Shen, Shanshan; Zou, Xiaoping; Krüger, Achim; Kleeff, Jörg; Michalski, Christoph W.; Friess, Helmut; Innocenti, Metello; Kong, Bo
Abstract:: Background & aims: Oncogenic KrasG12D 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 KrasG12D, 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 KrasG12D-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 KrasG12D-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 KrasG12D-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.
Stichworte:: BayBioMS; ADM; Arp2/3 Complex; PDAC; Rictor; Rptor; mTOR
Zeitschriftentitel:: Gastroenterology
Jahr:: 2021
Band / Volume:: 160
Heft / Issue:: 5
Seitenangaben Beitrag:: 1755-1770.e17
Volltext / DOI:: doi:10.1053/j.gastro.2020.12.061
Verlag / Institution:: Elsevier BV
E-ISSN:: 0016-5085
Publikationsdatum:: 01.04.2021
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Life Sciences Zentren Bayerisches Zentrum für Biomolekulare Massenspektrometrie (BayBioMS)Jahr 2021

mediaTUM Gesamtbestand Hochschulbibliographie 2021 Fakultäten Wissenschaftszentrum Weihenstephan Bayerisches Zentrum für Biomolekulare Massenspektrometrie (BayBioMS)