Targeting the AKT/mTOR pathway attenuates the metastatic potential of colorectal carcinoma circulating tumor cells in a murine xenotransplantation model

ABSTRACT: Circulating tumor cells (CTCs) play an important role in metastasis formation. Aberrant signaling of oncogenic pathways (e.g. PI3K/AKT/mTOR pathway) drives tumor progression. In this work, the susceptibility of the colon cancer CTC derived cell line, CTC-MCC-41, for AKT and mTOR inhibitors was evaluated. Additionally, the functional role of the expressed AKT isoforms was characterized in this cell line. The efficacy of AKT inhibitor MK2206, the mTOR inhibitor RAD001 and the combination was examined in CTC-MCC-41 cells in a murine intracardiac xenotransplantation model. Furthermore, stable isoform specific AKT1 or AKT2 knockdowns (KD) as well as AKT1/AKT2 double KD cells were generated. Differentially regulated proteins and phospho-peptides were identified using LC-MS. CTC-MCC-41 cells show a high susceptibility for dual targeting of AKT and mTOR in vivo indicating that selective eradication of CTCs may be considered as a new treatment option in cancer. KD of AKT1 or AKT2 significantly reduced the proliferation of CTC-MCC-41 cells. AKT KDs share commonly regulated proteins and phospho-proteins, but also regulate a large number uniquely. AKT1/AKT2 double KD cells show a strongly dysregulated replication machinery, as well as a decrease in cell cycle activity and stem cell associated processes underlining the non-redundant role of AKT isoforms.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Thomas Mair  

LAB HEAD: Daniel J. Smit, MD, PhD

PROVIDER: PXD054001 | Pride | 2025-04-14

REPOSITORIES: Pride