TY - JOUR
T1 - Roflumilast inhibits tumor growth and migration in STK11/LKB1 deficient pancreatic cancer
AU - Zhang, Shuman
AU - Yun, Duo
AU - Yang, Hao
AU - Eckstein, Markus
AU - Elbait, Gihan Daw
AU - Zhou, Yaxing
AU - Lu, Yanxi
AU - Yang, Hai
AU - Zhang, Jinping
AU - Dörflein, Isabella
AU - Britzen-Laurent, Nathalie
AU - Pfeffer, Susanne
AU - Stemmler, Marc P.
AU - Dahl, Andreas
AU - Mukhopadhyay, Debabrata
AU - Chang, David
AU - He, Hang
AU - Zeng, Siyuan
AU - Lan, Bin
AU - Frey, Benjamin
AU - Hampel, Chuanpit
AU - Lentsch, Eva
AU - Gollavilli, Paradesi Naidu
AU - Büttner, Christian
AU - Ekici, Arif B.
AU - Biankin, Andrew
AU - Schneider-Stock, Regine
AU - Ceppi, Paolo
AU - Grützmann, Robert
AU - Pilarsky, Christian
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41420-024-01890-y
DO - 10.1038/s41420-024-01890-y
M3 - Article
AN - SCOPUS:85187170279
SN - 2058-7716
VL - 10
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 124
ER -