ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2

In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2(KO)/TROP2(high) status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2(low)/TROP2(high) expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.

Automated summary

In colorectal cancer, low levels of ATF2 are associated with worse prognosis and tumor aggressiveness. TROP2 is identified as a novel inhibitory target gene of ATF2. In vitro studies demonstrated that high levels of TROP2 are critical for cell de-adhesion and increased cell migration. In vivo experiments confirmed that ATF2(KO)/TROP2(high) status promotes tumor invasiveness. Evaluation of ATF2(low)/TROP2(high) expression status may help identify high-risk CRC patients.