Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

Katharina Joechle; Huda Jumaa; Kerstin Thriene; Claus Hellerbrand; Birte Kulemann; Stefan Fichtner-Feigl; Sven A Lang; Jessica Guenzle

doi:10.3389/fcell.2021.785979

Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases

Front Cell Dev Biol. 2022 Jan 13:9:785979. doi: 10.3389/fcell.2021.785979. eCollection 2021.

Authors

Katharina Joechle^{1

2}, Huda Jumaa², Kerstin Thriene³, Claus Hellerbrand⁴, Birte Kulemann⁵, Stefan Fichtner-Feigl^{2

6}, Sven A Lang^{1

2}, Jessica Guenzle²

Affiliations

¹ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
² Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
³ Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
⁴ Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
⁵ Department of Surgery, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany.
⁶ Comprehensive Cancer Center Freiburg-CCCF, Medical Center-University, Freiburg, Germany.

Abstract

Cholangiocarcinoma (CCA) is a rare but highly aggressive tumor entity for which systemic therapies only showed limited efficacy so far. As OSI-027-a dual kinase inhibitor targeting both mTOR complexes, mTORC1 and mTORC2 - showed improved anti-cancer effects, we sought to evaluate its impact on the migratory and metastatic capacity of CCA cells in vitro. We found that treatment with OSI-027 leads to reduced cell mobility and migration as well as a reduced surviving fraction in colony-forming ability. While neither cell viability nor proliferation rate was affected, OSI-027 decreased the expression of MMP2 and MMP9. Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA.

Keywords: MTORC1/2; cholangiocarcinoma; invasion; matrix metalloproteinases; migration.