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

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Date

2022-08-01

Author

Huebner, Kerstin
Erlenbach-Wuensch, Katharina
Prochazka, Jan
Sheraj, Ilir
Hampel, Chuanpit
Mrazkova, Blanka
Michalcikova, Tereza
Tureckova, Jolana
Iatsiuk, Veronika
Weissmann, Anne
Ferrazzi, Fulvia
Kunze, Philipp
Nalli, Enise
Sammer, Elisabeth
Gehring, Annemarie
Cheema, Marie M.
Eckstein, Markus
Paap, Eva-Maria
Soederberg, Agnes
Fischer, Corinna
Paul, Sushmita
Mahadevan, Vijayalakshmi
Ndreshkjana, Benardina
Meier, Melanie A.
Muehlich, Susanne
Geppert, Carol I.
Merkel, Susanne
Grutzmann, Robert
Roehe, Adriana
Banerjee, Sreeparna
Hartmann, Arndt
Sedlacek, Radislav
Schneider-Stock, Regine

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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.

Subject Keywords

CAM model, De-adhesion, EMT, Intratumoral heterogeneity, Liver metastasis, Migration

URI

https://hdl.handle.net/11511/98520

Journal

Cellular and Molecular Life Sciences

DOI

https://doi.org/10.1007/s00018-022-04445-5

Collections

Department of Biology, Article

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Citation Formats

K. Huebner et al., “ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2,” Cellular and Molecular Life Sciences, vol. 79, no. 8, pp. 0–0, 2022, Accessed: 00, 2022. [Online]. Available: https://hdl.handle.net/11511/98520.