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

Gastroenterology. 2021 Apr;160(5):1755-1770.e17. doi: 10.1053/j.gastro.2020.12.061. Epub 2021 Jan 1.

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.

Keywords: ADM; Arp2/3 Complex; PDAC; Rictor; Rptor; mTOR.

MeSH terms

  • Acinar Cells / enzymology*
  • Acinar Cells / pathology
  • Actin-Related Protein 2-3 Complex / genetics
  • Actin-Related Protein 2-3 Complex / metabolism*
  • Animals
  • Carcinoma, Pancreatic Ductal / enzymology*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mechanistic Target of Rapamycin Complex 2 / genetics
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Metaplasia
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Pancreatic Ducts / enzymology*
  • Pancreatic Ducts / pathology
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Rapamycin-Insensitive Companion of mTOR Protein / genetics
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism
  • Regulatory-Associated Protein of mTOR / genetics
  • Regulatory-Associated Protein of mTOR / metabolism
  • Signal Transduction

Substances

  • Actin-Related Protein 2-3 Complex
  • KRAS protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • rictor protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)