Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1open access
- Authors
- Xu, Rong; Lee, Young-Joo; Kim, Chang-Hyeon; Min, Ga-Hong; Kim, Yeo-Bin; Park, Jung-Won; Kim, Dae-Hoon; Kim, Jung-Hyun; Yim, Hyungshin
- Issue Date
- Nov-2023
- Publisher
- BMC
- Keywords
- FoxM1; Invasiveness; Phosphorylation; PLK1; Tumor-associated macrophages
- Citation
- Journal of Experimental & Clinical Cancer Research, v.42, no.1, pp 1 - 25
- Pages
- 25
- Indexed
- SCIE
- Journal Title
- Journal of Experimental & Clinical Cancer Research
- Volume
- 42
- Number
- 1
- Start Page
- 1
- End Page
- 25
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/115640
- DOI
- 10.1186/s13046-023-02872-1
- ISSN
- 1756-9966
1756-9966
- Abstract
- Background: Understanding the mechanism behind immune cell plasticity in cancer metastasis is crucial for identifying key regulators. Previously we found that mitotic factors regulate epithelial-mesenchymal transition, but how these factors convert to metastatic players in the tumor microenvironment (TME) is not fully understood. Methods: The clinical importance of mitotic factors was analyzed by heatmap analysis, a KM plot, and immunohistochemistry in lung adenocarcinoma (LUAD) patients. Immunoprecipitation, LC–MS/MS, kinase assay, and site-directed mutagenesis were performed for the interaction and phosphorylation. A tail-vein injection mouse model, Transwell-based 3D culture, microarray analysis, coculture with monocytes, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated FoxM1 in metastasis of TME. Results: The phosphorylated FoxM1 at Ser25 by PLK1 acquires the reprogramming ability to stimulate the invasive traits in cancer and influence immune cell plasticity. This invasive form of p-FoxM1 upregulates the expression of IL1A/1B, VEGFA, and IL6 by direct activation, recruiting monocytes and promoting the polarization of M2d-like tumor-associated macrophages (TAMs). Upregulation of PD-L1 in LUAD having phosphomimetic FoxM1 facilitates immune evasion. In invasive LUAD with phosphomimetic FoxM1, IFITM1 is the most highly expressed through the activation of the STING-TBK1-IRF3 signaling, which enhances FoxM1-mediated signaling. Clinically, higher expression of FOXM1, PLK1, and IFITM1 is inversely correlated with the survival rate of advanced LUAD patients, providing a promising therapeutic strategy for the treatment of LUAD. Conclusion: FoxM1-based therapy would be a potential therapeutic strategy for LUAD to reduce TAM polarization, immune escape, and metastasis, since FoxM1 functions as a genetic reprogramming factor reinforcing LUAD malignancy in the TME. © 2023, The Author(s).
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