mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote Kras G12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis
| Autor: | Zhiheng Zhang, Jörg Kleeff, Nadja Maeritz, Susanne Raulefs, Xiaoping Zou, Helmut Friess, Christina Ludwig, Dianbo Yao, Kathleen Schuck, Metello Innocenti, Yamin Zhao, Shanshan Shen, Vivien Tissen, Achim Krüger, Christoph W. Michalski, Jan G. D’Haese, Rob A. van der Kammen, Carsten Jäger, Benjamin Schoeps, Anna Melissa Schlitter, Bo Kong |
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| Přispěvatelé: | Zhao, Y, Schoeps, B, Yao, D, Zhang, Z, Schuck, K, Tissen, V, Jäger, C, Schlitter, A, van der Kammen, R, Ludwig, C, D'Haese, J, Raulefs, S, Maeritz, N, Shen, S, Zou, X, Krüger, A, Kleeff, J, Michalski, C, Friess, H, Innocenti, M, Kong, B |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
ADM Arp2/3 complex macromolecular substances mTORC1 mTORC2 Filamentous actin Rictor 03 medical and health sciences 0302 clinical medicine Neoplastic transformation Mechanistic target of rapamycin PI3K/AKT/mTOR pathway Hepatology biology Chemistry Gastroenterology PDAC Actin cytoskeleton Cell biology Arp2/3 Complex 030104 developmental biology Rptor biology.protein mTOR 030211 gastroenterology & hepatology biological phenomena cell phenomena and immunity |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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