Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer

Zhang S, Yun D, Yang H, Eckstein M, Elbait GD, Zhou Y, Lu Y, Yang H, Zhang J, Dörflein I, Britzen-Laurent N, Pfeffer S, Stemmler M, Dahl A, Mukhopadhyay D, Chang D, He H, Zeng S, Lan B, Frey B, Hampel C, Lentsch E, Gollavilli PN, Büttner C, Ekici AB, Biankin A, Schneider-Stock R, Ceppi P, Grützmann R, Pilarsky C (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Cell Death Discovery Nature Publishing Group

Book Volume: 10

Article Number: 124

Journal Issue: 1

DOI: 10.1038/s41420-024-01890-y

Abstract

Pancreatic cancer is a malignant tumor of the digestive system. It is highly aggressive, easily metastasizes, and extremely difficult to treat. This study aimed to analyze the genes that might regulate pancreatic cancer migration to provide an essential basis for the prognostic assessment of pancreatic cancer and individualized treatment. A CRISPR knockout library directed against 915 murine genes was transfected into TB 32047 cell line to screen which gene loss promoted cell migration. Next-generation sequencing and PinAPL.py- analysis was performed to identify candidate genes. We then assessed the effect of serine/threonine kinase 11 (STK11) knockout on pancreatic cancer by wound-healing assay, chick agnosia (CAM) assay, and orthotopic mouse pancreatic cancer model. We performed RNA sequence and Western blotting for mechanistic studies to identify and verify the pathways. After accelerated Transwell migration screening, STK11 was identified as one of the top candidate genes. Further experiments showed that targeted knockout of STK11 promoted the cell migration and increased liver metastasis in mice. Mechanistic analyses revealed that STK11 knockout influences blood vessel morphogenesis and is closely associated with the enhanced expression of phosphodiesterases (PDEs), especially PDE4D, PDE4B, and PDE10A. PDE4 inhibitor Roflumilast inhibited STK11-KO cell migration and tumor size, further demonstrating that PDEs are essential for STK11-deficient cell migration. Our findings support the adoption of therapeutic strategies, including Roflumilast, for patients with STK11-mutated pancreatic cancer in order to improve treatment efficacy and ultimately prolong survival.

Authors with CRIS profile

Shuman Zhang Professur für Chirurgische Forschung Duo Yun Professur für Chirurgische Forschung Hao Yang Professur für Experimentelle Tumorpathologie Markus Eckstein Institute of Pathology Yaxing Zhou Professur für Chirurgische Forschung Yanxi Lu Department of Surgery Hai Yang Department of Surgery Jinping Zhang Professur für Chirurgische Forschung Nathalie Britzen-Laurent Medizinische Fakultät Marc Stemmler Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Benjamin Frey Department of Radiation Oncology Chuanpit Hampel Institute of Pathology Eva Lentsch Department of Surgery Christian Büttner Lehrstuhl für Humangenetik Arif Bülent Ekici Institute of Human Genetics Regine Schneider-Stock Professur für Experimentelle Tumorpathologie Robert Grützmann Lehrstuhl für Allgemein- und Viszeralchirurgie Christian Pilarsky Professur für Chirurgische Forschung

Involved external institutions

University of Southern Denmark / Syddansk Universitet DK Denmark (DK) Fudan University / 复旦大学 CN China (CN) University of Glasgow GB United Kingdom (GB) Khalifa University of Science, Technology & Research (KUSTAR) / جامعة خليفة AE United Arab Emirates (AE) Technische Universität Dresden DE Germany (DE) Mayo Clinic College of Medicine and Science (MCCMS) US United States (USA) (US) Hunan Provincial People’s Hospital / 湖南省人民医院 CN China (CN)

How to cite

APA:

Zhang, S., Yun, D., Yang, H., Eckstein, M., Elbait, G.D., Zhou, Y.,... Pilarsky, C. (2024). Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer. Cell Death Discovery, 10(1). https://doi.org/10.1038/s41420-024-01890-y

MLA:

Zhang, Shuman, et al. "Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer." Cell Death Discovery 10.1 (2024).

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