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

K. Huebner, K. Erlenbach-Wuensch, J. Prochazka, I. Sheraj, C. Hampel, B. Mrazkova, T. Michalcikova, J. Tureckova, V. Iatsiuk, A. Weissmann, F. Ferrazzi, P. Kunze, E. Nalli, E. Sammer, A. Gehring, MM. Cheema, M. Eckstein, EM. Paap, A. Soederberg,...

. 2022 ; 79 (8) : 423. [pub] 20220715

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc22025206

Grantová podpora
SCHN477/18-1 Deutsche Forschungsgemeinschaft
CA17118 European Cooperation in Science and Technology
LM2015040 Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences
RVO 68378050 Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences
Z.1.05/1.1.00/02.0109 Univerzita Karlova v Praze

E-zdroje Online Plný text

NLK PubMed Central od 1997
ProQuest Central od 1997-01-01 do Před 1 rokem
Medline Complete (EBSCOhost) od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 1997-01-01 do Před 1 rokem

Odkazy

PubMed 35838828
DOI 10.1007/s00018-022-04445-5
Knihovny.cz E-zdroje

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 ATF2KO/TROP2high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2low/TROP2high 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.

Citace poskytuje Crossref.org

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