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

0559440 - ÚMG 2023 RIV CH eng J - Journal Article
Huebner, K. - Erlenbach-Wuensch, K. - Procházka, Jan - Sheraj, I. - Hampel, C. - Mrázková, Blanka - Michalčíková, Tereza - Turečková, Jolana - Iatsiuk, Veronika - Weissmann, A. - Ferrazzi, F. - Kunze, P. - Nalli, E. - Sammer, E. - Gehring, A. - Cheema, Marie Munawar - Eckstein, M. - Paap, E.M. - Soederberg, A. - Fischer, C. - Paul, S. - Mahadevan, V. - Ndreshkjana, B. - Meier, M.A. - Muehlich, S. - Geppert, C. - Merkel, S. - Grutzmann, R. - Roehe, A. - Banerjee, S. - Schneider‑Stock, R. … Total 33 authors
ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2.
Cellular and Molecular Life Sciences. Roč. 79, č. 8 (2022), č. článku 423. ISSN 1420-682X. E-ISSN 1420-9071
R&D Projects: GA MŠMT(CZ) LM2015040; GA MŠMT EF16_013/0001789; GA MŠMT(CZ) ED1.1.00/02.0109; GA MŠMT ED2.1.00/19.0395
Institutional support: RVO:68378050
Keywords : De-adhesion * Migration * Intratumoral heterogeneity * Liver metastasis * emt * CAM model
OECD category: Biochemistry and molecular biology
Impact factor: 8, year: 2022
Method of publishing: Open access
https://link.springer.com/article/10.1007/s00018-022-04445-5

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.
Permanent Link: https://hdl.handle.net/11104/0332857