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

Hübner K, Erlenbach-Wünsch K, Prochazka J, Sheraj I, Hampel C, Mrazkova B, Michalcikova T, Tureckova J, Iatsiuk V, Weissmann A, Ferrazzi F, Kunze P, Nalli E, Sammer E, Gehring A, Cheema MM, Eckstein M, Paap EM, Söderberg A, Fischer C, Paul S, Mahadevan V, Ndreshkjana B, Meier M, Mühlich S, Geppert CI, Merkel S, Grützmann R, Roehe A, Banerjee S, Hartmann A, Sedlacek R, Schneider-Stock R (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cellular and Molecular Life Sciences Springer

Book Volume: 79

Journal Issue: 8

DOI: 10.1007/s00018-022-04445-5

Abstract

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.

Authors with CRIS profile

Kerstin Hübner Institute of Pathology Katharina Erlenbach-Wünsch Medizinische Fakultät Chuanpit Hampel Institute of Pathology Fulvia Ferrazzi Department of Nephropathology Philipp Kunze Institute of Pathology Enise Nalli Professur für Experimentelle Tumorpathologie Markus Eckstein Institute of Pathology Eva-Maria Paap Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Agnes Söderberg Lehrstuhl für Biochemie und Molekulare Medizin Benardina Ndreshkjana Institute of Pathology Melanie Meier Professur für Molekulare und Klinische Pharmazie Susanne Mühlich Professur für Molekulare und Klinische Pharmazie Carol-Immanuel Geppert Institute of Pathology Susanne Merkel Department of Surgery Robert Grützmann Lehrstuhl für Allgemein- und Viszeralchirurgie Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Regine Schneider-Stock Professur für Experimentelle Tumorpathologie

Involved external institutions

Institute of Molecular Genetics of the ASCR / Ústav molekulární genetiky AV ČR CZ Czech Republic (CZ) Middle East Technical University (METU) / Orta Doğu Teknik Üniversitesi TR Turkey (TR) Indian Institute of Technology Jodhpur IN India (IN) Universidade Federal de Ciências da Saúde de Porto Alegre BR Brazil (BR) Institute of Bioinformatics and Applied Biotechnology (IBAB) IN India (IN)

How to cite

APA:

Hübner, K., Erlenbach-Wünsch, K., Prochazka, J., Sheraj, I., Hampel, C., Mrazkova, B.,... Schneider-Stock, R. (2022). ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2. Cellular and Molecular Life Sciences, 79(8). https://doi.org/10.1007/s00018-022-04445-5

MLA:

Hübner, Kerstin, et al. "ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2." Cellular and Molecular Life Sciences 79.8 (2022).

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