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ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2
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SYSNO ASEP 0559440 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2 Author(s) Huebner, K. (DE)
Erlenbach-Wuensch, K. (DE)
Procházka, Jan (UMG-J) ORCID
Sheraj, I. (TR)
Hampel, C. (DE)
Mrázková, Blanka (UMG-J)
Michalčíková, Tereza (UMG-J)
Turečková, Jolana (UMG-J) RID
Iatsiuk, Veronika (UMG-J)
Weissmann, A. (DE)
Ferrazzi, F. (DE)
Kunze, P. (DE)
Nalli, E. (DE)
Sammer, E. (DE)
Gehring, A. (DE)
Cheema, Marie Munawar (UMG-J)
Eckstein, M. (DE)
Paap, E.M. (DE)
Soederberg, A. (DE)
Fischer, C. (DE)
Paul, S. (IN)
Mahadevan, V. (IN)
Ndreshkjana, B. (DE)
Meier, M.A. (DE)
Muehlich, S. (DE)
Geppert, C. (DE)
Merkel, S. (DE)
Grutzmann, R. (DE)
Roehe, A. (BR)
Banerjee, S. (TR)
Schneider‑Stock, R. (DE)Number of authors 33 Article number 423 Source Title Cellular and Molecular Life Sciences - ISSN 1420-682X
Roč. 79, č. 8 (2022)Number of pages 17 s. Publication form Online - E Language eng - English Country CH - Switzerland Keywords De-adhesion ; Migration ; Intratumoral heterogeneity ; Liver metastasis ; emt ; CAM model Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects LM2015040 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001789 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000826018000001 DOI 10.1007/s00018-022-04445-5 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://link.springer.com/article/10.1007/s00018-022-04445-5
Number of the records: 1