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Open AccessArticle

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer

1
Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany
2
Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, 35043 Marburg, Germany
3
Institute of Pathology, University of Tübingen, 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Equal contributing senior authors.
Academic Editor: Alexander Arlt
Cancers 2021, 13(4), 725; https://doi.org/10.3390/cancers13040725
Received: 5 January 2021 / Revised: 26 January 2021 / Accepted: 7 February 2021 / Published: 10 February 2021
Unraveling the mechanistic regulations that influence tumor behavior is an important step towards treatment. However, in vitro studies capture only small parts of the complex signaling cascades leading to tumor development. Mechanistic modeling, instead, allows a more holistic view of complex signaling pathways and their crosstalk. These models are able to suggest mechanistic regulations that can be validated by targeted and thus more cost-effective experiments. This article presents a logical model of pancreatic cancer cells with high cofilin-1 expression. The model includes migratory, proliferative, and apoptotic pathways as well as their crosstalk. Based on this model, mechanistic regulations affecting tumor promotion could be unraveled. Moreover, it was applied to screen for new therapeutic targets. The development of resistance mechanisms is a common limitation of cancer therapies. Therefore, new approaches are needed to identify optimal treatments. One is suggested in this article, indicating the surface protein CD44 as a promising target.
Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression. View Full-Text
Keywords: pancreatic cancer; cofilin-1; modeling; molecular mechanism; Boolean networks; predicting therapeutic targets pancreatic cancer; cofilin-1; modeling; molecular mechanism; Boolean networks; predicting therapeutic targets
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MDPI and ACS Style

Werle, S.D.; Schwab, J.D.; Tatura, M.; Kirchhoff, S.; Szekely, R.; Diels, R.; Ikonomi, N.; Sipos, B.; Sperveslage, J.; Gress, T.M.; Buchholz, M.; Kestler, H.A. Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer. Cancers 2021, 13, 725. https://doi.org/10.3390/cancers13040725

AMA Style

Werle SD, Schwab JD, Tatura M, Kirchhoff S, Szekely R, Diels R, Ikonomi N, Sipos B, Sperveslage J, Gress TM, Buchholz M, Kestler HA. Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer. Cancers. 2021; 13(4):725. https://doi.org/10.3390/cancers13040725

Chicago/Turabian Style

Werle, Silke D.; Schwab, Julian D.; Tatura, Marina; Kirchhoff, Sandra; Szekely, Robin; Diels, Ramona; Ikonomi, Nensi; Sipos, Bence; Sperveslage, Jan; Gress, Thomas M.; Buchholz, Malte; Kestler, Hans A. 2021. "Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer" Cancers 13, no. 4: 725. https://doi.org/10.3390/cancers13040725

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