Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1
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 microenv...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02872-1 |
| _version_ | 1827707665651859456 |
|---|---|
| author | Rong Xu Young-Joo Lee Chang-Hyeon Kim Ga-Hong Min Yeo-Bin Kim Jung-Won Park Dae-Hoon Kim Jung-Hyun Kim Hyungshin Yim |
| author_facet | Rong Xu Young-Joo Lee Chang-Hyeon Kim Ga-Hong Min Yeo-Bin Kim Jung-Won Park Dae-Hoon Kim Jung-Hyun Kim Hyungshin Yim |
| author_sort | Rong Xu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T16:50:41Z |
| format | Article |
| id | doaj.art-5160280061be4f78afecbecb53ccef5e |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-10T16:50:41Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-5160280061be4f78afecbecb53ccef5e2023-11-20T11:18:22ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-11-0142112510.1186/s13046-023-02872-1Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1Rong Xu0Young-Joo Lee1Chang-Hyeon Kim2Ga-Hong Min3Yeo-Bin Kim4Jung-Won Park5Dae-Hoon Kim6Jung-Hyun Kim7Hyungshin Yim8Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityDivision of Intractable Diseases Research, Department of Chronic Diseases Convergence Research, Korea National Institute of HealthDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang UniversityAbstract 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.https://doi.org/10.1186/s13046-023-02872-1FoxM1PhosphorylationPLK1InvasivenessTumor-associated macrophages |
| spellingShingle | Rong Xu Young-Joo Lee Chang-Hyeon Kim Ga-Hong Min Yeo-Bin Kim Jung-Won Park Dae-Hoon Kim Jung-Hyun Kim Hyungshin Yim Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 Journal of Experimental & Clinical Cancer Research FoxM1 Phosphorylation PLK1 Invasiveness Tumor-associated macrophages |
| title | Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 |
| title_full | Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 |
| title_fullStr | Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 |
| title_full_unstemmed | Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 |
| title_short | Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 |
| title_sort | invasive foxm1 phosphorylated by plk1 induces the polarization of tumor associated macrophages to promote immune escape and metastasis amplified by ifitm1 |
| topic | FoxM1 Phosphorylation PLK1 Invasiveness Tumor-associated macrophages |
| url | https://doi.org/10.1186/s13046-023-02872-1 |
| work_keys_str_mv | AT rongxu invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT youngjoolee invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT changhyeonkim invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT gahongmin invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT yeobinkim invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT jungwonpark invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT daehoonkim invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT junghyunkim invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 AT hyungshinyim invasivefoxm1phosphorylatedbyplk1inducesthepolarizationoftumorassociatedmacrophagestopromoteimmuneescapeandmetastasisamplifiedbyifitm1 |