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FSCN1 induced PTPRF-dependent tumor microenvironment inflammatory reprogramming promotes lung adenocarcinoma progression via regulating macrophagic glycolysis

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Abstract

Purpose

Macrophages (MΦs) play a dual role in the promotion and suppression of lung adenocarcinoma (LUAD), the function of which is influenced by the metabolic status. The role of protein tyrosine phosphatase receptor type F (PTPRF) in cancer has not been elucidated, and its role in MΦs remains to be seen.

Methods

The Seahorse XFe 96 Cell Flow Analyzer detected glucose metabolism in tumor cells and macrophages. The expressions of FSCN1, M-CSF, IL4, PTPRF and IGF1 in macrophages were detected by Western blotting and qRT-PCR. Binding of FSCN1 and IGF1R was detected by co-immunoprecipitation. The tumor status in animals was observed using the IVIS Lumina III imaging system.

Results

We found that Fascin Actin-Bundling Protein 1 (FSCN1) activates the PI3K-AKT and JAK-STAT signaling pathways in LUAD cells via binding to IGF-1R, thereby promoting the secretion of cytokines such as IL4 and M-CSF. IL4 and M-CSF promote the expression of PTPRF in MΦs, leading to M2 polarization of MΦs by increasing glucose intake and lactate production. In return, M2-type MΦs act on LUAD cells by secreting cytokines such as IGF-1, CCL2, and IL10, which ultimately promote tumor progression. In vivo experiments proved that the knockdown of FSCN1 in A549 cells and PTPRF in MΦs greatly reduced LUAD proliferative and metastatic capacity, which was consistent with the in vitro findings.

Conclusions

This study investigated the reprogramming effects of FSCN1 and PTPRF on inflammatory cytokines in the LUAD microenvironment, revealing potential mechanisms by which FSCN1 and PTPRF promote tumor progression and providing a new experimental basis for LUAD treatment.

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Data availability

The inquiry of original data can be directed to the corresponding authors for rational reasons.

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Funding

This research was funded by the National Natural Science Foundation of China (No. 82203645), the Yangfan plan program of Shanghai (No. 22YF107300), Special Foundation for Supporting Biomedical Technology of Shanghai, China (No. 22S11900300), and the Research Foundation of Shanghai Municipal Health Commission (No. 20204Y0228).

Author information

Author notes

  1. Yiwei Huang, Guangyao Shan, and Yanjun Yi contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China

    Yiwei Huang, Guangyao Shan, Yanjun Yi, Jiaqi Liang, Zhengyang Hu, Guoshu Bi, Zhencong Chen, Junjie Xi, Di Ge, Qun Wang, Lijie Tan, Wei Jiang & Cheng Zhan

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  1. Yiwei Huang
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Contributions

(I) Conception and design were contributed by Cheng Zhan, Wei Jiang, and Qun Wang;

(II) Administrative support was contributed by Di Ge, Lijie Tan, and Cheng Zhan;

(III) Experiments were conducted by and Yiwei Huang, Yanjun Yi, and Guangyao Shan;

(IV) Collection and assembly of data were contributed by Guangyao Shan, and Guoshu Bi;

(V) Data analysis and interpretation were contributed by Guangyao Shan, Jiaqi Liang, Guoshu Bi, Zhengyang Hu, Zhencong Chen, and Junjie Xi;

(VI) Manuscript writing was contributed by all authors;

(VII) Final approval of manuscript was contributed by all authors.

Corresponding authors

Correspondence to Wei Jiang or Cheng Zhan.

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The authors declare no competing interests.

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and was approved by the ethical committees of Zhongshan Hospital (approval number: B2021-136).

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Supplementary Information

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13402_2022_726_MOESM1_ESM.jpg

Supplementary figure 1 (a) Western blot showed the expression changing of Stat1, Stat5, Stat6, p-Stat1, p-Stat5, p-Stat6 after knocking down the FSCN1. (b,c) ELISA showed changes in the content of M-CSF and IL4 secreted by A549 after knockdown of FSCN1. (d) Flow cytometry detected the effect of the M-CSF and IL4 on macrophage polarization when they added to the culture supernatant of FSCN1-knockdown A549 cells. (JPG 1081 KB)

13402_2022_726_MOESM2_ESM.jpg

Supplementary figure 2 (a) Heatmap of the top 50 DEGs of macrophages (derived from THP-1 cells) cocultured with FCSN1-knockdown or control A549 cells. (b) The volcano plot of the DEGs of macrophages (derived from THP-1 cells) cocultured with FCSN1-knockdown or control A549 cells. (c) The expression level of PTPRF in tumor tissue and adjacent normal tissue of LUAD. (d) Kaplan-Meier survival analysis between the LUAD patients from TCGA with different PTPRF expression levels. (e) The Spearman correlation analysis between FSCN1 expression level and macrophage infiltration level. (f) The Spearman correlation analysis between FSCN1 expression level and FSCN1 expression level. TCGA, The Cancer Genome Atlas. *, p < 0.05. (JPG 2131 KB)

13402_2022_726_MOESM3_ESM.jpg

Supplementary figure 3 (a) Statistical analysis of flow cytometry results of Figure 3k. (b) Western blot showed the effect of overexpression of PTPRF on the expression of GLUT1 on the membrane protein of M2-type macrophages. (c) Western blot showed the effect of overexpression of PTPRF on the polarization of MΦ in the absence of glucose. (JPG 810 KB)

13402_2022_726_MOESM4_ESM.jpg

Supplementary figure 4 Effect of PI3K-AKT signaling pathway on A549 glycolysis detected by Seahorse XFe 96 energy analyzer. (JPG 752 KB)

Supplementary figure 5 RT-PCR detected the expression levels of PTPRF in THP-1, A549, H1975, and H1395. (JPG 715 KB)

Supplementary Table 1 (DOCX 23 KB)

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Huang, Y., Shan, G., Yi, Y. et al. FSCN1 induced PTPRF-dependent tumor microenvironment inflammatory reprogramming promotes lung adenocarcinoma progression via regulating macrophagic glycolysis. Cell Oncol. 45, 1383–1399 (2022). https://doi.org/10.1007/s13402-022-00726-0

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