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AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

1
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
2
Oncode Institute, 3521 AL Utrecht, The Netherlands
3
Dipartimento di Medicina e Chirurgia Traslazionale, Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, 20123 Milano, Italy
4
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
5
Cellular and Molecular Oncology Section, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, 90127 Palermo, Italy
6
Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, 81520-260 Curitiba, Brazil
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
Academic Editor: Daniel Louvard
Cancers 2021, 13(4), 801; https://doi.org/10.3390/cancers13040801
Received: 8 January 2021 / Revised: 5 February 2021 / Accepted: 9 February 2021 / Published: 14 February 2021
(This article belongs to the Section Clinical Trials of Cancer)
Colorectal cancer can be subdivided into four distinct subtypes that are characterised by different clinical features and responses to therapies currently used in the clinic to treat this disease. One of those subtypes, called CMS4, is associated with a worse prognosis and poor response to therapies compared to other subtypes. We therefore set out to explore what proteins are differentially expressed and used in CMS4 to find potential new targets for therapy. We found that protein AKT3 is highly expressed in CMS4, and that active AKT3 inhibits a protein that stalls growth of cancer cells (p27KIP1). We can target AKT3 with inhibitors which leads to strongly reduced growth of cancer cell lines that are categorised as CMS4. Furthermore, our data suggests that high AKT3 expression in tumour cells may be used to identify poor prognosis colorectal cancer patients. Future research should point out if high AKT3 expression can be used to select colorectal cancer patients that have a poor prognosis but that could benefit from AKT3-targeted treatment.
Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy. View Full-Text
Keywords: mesenchymal CRC; CMS; AKT3; growth mesenchymal CRC; CMS; AKT3; growth
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MDPI and ACS Style

Buikhuisen, J.Y.; Gomez Barila, P.M.; Torang, A.; Dekker, D.; de Jong, J.H.; Cameron, K.; Vitale, S.; Stassi, G.; van Hooff, S.R.; Castro, M.A.A.; Vermeulen, L.; Medema, J.P. AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition. Cancers 2021, 13, 801. https://doi.org/10.3390/cancers13040801

AMA Style

Buikhuisen JY, Gomez Barila PM, Torang A, Dekker D, de Jong JH, Cameron K, Vitale S, Stassi G, van Hooff SR, Castro MAA, Vermeulen L, Medema JP. AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition. Cancers. 2021; 13(4):801. https://doi.org/10.3390/cancers13040801

Chicago/Turabian Style

Buikhuisen, Joyce Y., Patricia M. Gomez Barila, Arezo Torang, Daniëlle Dekker, Joan H. de Jong, Kate Cameron, Sara Vitale, Giorgio Stassi, Sander R. van Hooff, Mauro A. A. Castro, Louis Vermeulen, and Jan Paul Medema. 2021. "AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition" Cancers 13, no. 4: 801. https://doi.org/10.3390/cancers13040801

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