Untargeted metabolomics yields insight into extramammary Paget's disease mechanisms

Long Jiang; Xiaoxiang Xu; Guorong Yan; Yuhao Wu; Ningyuan Xi; Yongxian Lai; Guolong Zhang; Yeqiang Liu

doi:10.3389/fonc.2024.1319819

Untargeted metabolomics yields insight into extramammary Paget's disease mechanisms

Front Oncol. 2024 Jan 29:14:1319819. doi: 10.3389/fonc.2024.1319819. eCollection 2024.

Authors

Long Jiang^#^{1

2}, Xiaoxiang Xu^#^{2

3}, Guorong Yan^{2

4

5}, Yuhao Wu^{2

4

5}, Ningyuan Xi^{2

3}, Yongxian Lai^{1

2}, Guolong Zhang^{2

4

5}, Yeqiang Liu^{2

3}

Affiliations

¹ Department of Dermatologic Surgery, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
² Skin Cancer Center, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
³ Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
⁴ Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
⁵ Institute of Photomedicine, School of Medicine, Tongji University, Shanghai, China.

^# Contributed equally.

Abstract

Background: Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy, commonly affecting the external genitalia and perianal area of the elderly with unclear pathogenesis. Metabolomics provides a novel perspective for uncovering the metabolic mechanisms of a verity of cancers.

Materials and methods: Here, we explored the metabolome of EMPD using an untargeted strategy. In order to further investigate the potential relationship between metabolites and gene expression, we re-analyzed the gene expression microarray data (GSE117285) using differential expression analysis and functional enrichment analyses.

Results: Results showed that a total of 896 metabolites were identified and 87 metabolites including 37 upregulated and 50 downregulated significantly in EMPD were sought out. In the following feature selection analyses, four metabolites, namely, cyclopentyl fentanyl-d5, LPI 17:0, guanosine-3',5'-cyclic monophosphate, kynurenine (KYN, high in EMPD) were identified by both random forest and support vector machine analyses. We then identified 1,079 dysfunctional genes: 646 upregulated and 433 downregulated in EMPD. Specifically, the tryptophan-degrading enzyme including indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) were also increased. Generally, cancers exhibit a high expression of IDO1 and TDO2 to catabolize tryptophan, generating abundant KYN. Moreover, we also noticed the abnormal activation of sustaining proliferative signaling in EMPD.

Conclusion: In conclusion, this study was the first to reveal the metabolome profile of EMPD. Our results demonstrate that IDO1/TDO2-initialized KYN metabolic pathway may play a vital role in the development and progression of EMPD, which may serve as a potential therapeutic target for treating EMPD.

Keywords: IDO1; TDO2; extramammary Paget’s disease; kynurenine pathway; untargeted metabolomics.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was financially founded by the National Natural Science Foundation of China (82073016 and 82203942), the Shanghai Natural Science Foundation (20ZR1449400, 22ZR1455500 and 23ZR1456100).