Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer
Abstract Background Muscle invasive bladder cancer (MIBC) is a life-threatening malignant tumor characterized by high metastasis rates, poor prognosis, and limited treatment options. Immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 represent an emerging treatment for MIBC immunotherapy....
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BMC
2024-10-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-05685-8 |
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| author | Yaobang Wang Wuyue Song Chao Feng Shulin Wu Zezu Qin Tao Liu Yu Ye Rong Huang Yuanliang Xie Zhong Tang Qiuyan Wang Tianyu Li |
| author_facet | Yaobang Wang Wuyue Song Chao Feng Shulin Wu Zezu Qin Tao Liu Yu Ye Rong Huang Yuanliang Xie Zhong Tang Qiuyan Wang Tianyu Li |
| author_sort | Yaobang Wang |
| collection | DOAJ |
| description | Abstract Background Muscle invasive bladder cancer (MIBC) is a life-threatening malignant tumor characterized by high metastasis rates, poor prognosis, and limited treatment options. Immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 represent an emerging treatment for MIBC immunotherapy. However, the characteristics of patients likely to benefit from immunotherapy remain unclear. Methods We performed single-cell mass cytometry (CyTOF) analysis of 179,483 single cells to characterize potential immunotherapy-related cancer stem cells (CSCs)-like populations in the tumor microenvironment of 38 MIBC tissues. The upregulated expression of IGF2BP3 in CD274 + ALDH + CSC-like cells, which was associated with poor clinical prognosis, was analyzed by bulk RNA-sequencing data from an in-house cohort. The functional role of IGF2BP3 was determined through cell proliferation, colony formation, cell apoptosis and sphere formation assays. The regulation of SPHK1 expression by IGF2BP3 was investigated using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and bulk RNA-sequencing (bulk RNA-seq). We further utilized single-nucleus RNA sequencing (snRNA-seq) data from 67,988 cells of 25 MIBC tissues and single-cell RNA sequencing (scRNA-seq) data from MIBC patient-derived organoids to characterize the molecular features of bladder cancer cells co-expressing IGF2BP3 and SPHK1. Spatial transcriptomics (ST) and co-detection by indexing (CODEX) analysis were used to describe the spatial distribution and interactions of IGF2BP3 + SPHK1 + bladder cancer cells and immune cells. Results A subset of CD274 + ALDH + CSC-like cells was identified, associating with immunosuppression and low survival rates in MIBC patients. IGF2BP3, an m6A reader gene, was found to be upregulated in the CD274 + ALDH + CSC-like cell population and linked to poor clinical prognosis in MIBC. Knockout of IGF2BP3 dramatically promoted cell apoptosis and reduced cell proliferation in T24 cells. By integrating MeRIP-seq and bulk RNA-seq analyses, we identified SPHK1 served as a substrate for IGF2BP3 in an m6A-dependent manner. Further snRNA-seq, scRNA-seq, ST, and CODEX analysis revealed a closer topographical distance between IGF2BP3 + SPHK1 + bladder cancer cells and exhausted CD8 + T cells, providing one explanation for the superior response to immunotherapy in IGF2BP3 + SPHK1 + bladder cancer cells-enriched patients. Finally, an ICI-associated signature was developed based on the enriched genes of IGF2BP3 + SPHK1 + bladder cancer cells, and its potential ability to predict the response to immunotherapy was validated in two independent immunotherapy cohort. Conclusions Our study highlighted the critical involvement of the IGF2BP3/SPHK1 signaling in maintaining the stemness of CSCs and promoting MIBC progression. Additionally, these findings suggested that the IGF2BP3/SPHK1 signaling might serve as a biomarker for prognosis and immunotherapy response in MIBC. |
| format | Article |
| id | doaj-art-66d5d50d0ee7434fa561093f7a3473c6 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-66d5d50d0ee7434fa561093f7a3473c62025-08-20T04:03:06ZengBMCJournal of Translational Medicine1479-58762024-10-0122112110.1186/s12967-024-05685-8Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancerYaobang Wang0Wuyue Song1Chao Feng2Shulin Wu3Zezu Qin4Tao Liu5Yu Ye6Rong Huang7Yuanliang Xie8Zhong Tang9Qiuyan Wang10Tianyu Li11Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical UniversityInstitute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical UniversityInstitute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityGuangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical UniversityDepartment of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical UniversityInstitute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical UniversityAbstract Background Muscle invasive bladder cancer (MIBC) is a life-threatening malignant tumor characterized by high metastasis rates, poor prognosis, and limited treatment options. Immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 represent an emerging treatment for MIBC immunotherapy. However, the characteristics of patients likely to benefit from immunotherapy remain unclear. Methods We performed single-cell mass cytometry (CyTOF) analysis of 179,483 single cells to characterize potential immunotherapy-related cancer stem cells (CSCs)-like populations in the tumor microenvironment of 38 MIBC tissues. The upregulated expression of IGF2BP3 in CD274 + ALDH + CSC-like cells, which was associated with poor clinical prognosis, was analyzed by bulk RNA-sequencing data from an in-house cohort. The functional role of IGF2BP3 was determined through cell proliferation, colony formation, cell apoptosis and sphere formation assays. The regulation of SPHK1 expression by IGF2BP3 was investigated using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and bulk RNA-sequencing (bulk RNA-seq). We further utilized single-nucleus RNA sequencing (snRNA-seq) data from 67,988 cells of 25 MIBC tissues and single-cell RNA sequencing (scRNA-seq) data from MIBC patient-derived organoids to characterize the molecular features of bladder cancer cells co-expressing IGF2BP3 and SPHK1. Spatial transcriptomics (ST) and co-detection by indexing (CODEX) analysis were used to describe the spatial distribution and interactions of IGF2BP3 + SPHK1 + bladder cancer cells and immune cells. Results A subset of CD274 + ALDH + CSC-like cells was identified, associating with immunosuppression and low survival rates in MIBC patients. IGF2BP3, an m6A reader gene, was found to be upregulated in the CD274 + ALDH + CSC-like cell population and linked to poor clinical prognosis in MIBC. Knockout of IGF2BP3 dramatically promoted cell apoptosis and reduced cell proliferation in T24 cells. By integrating MeRIP-seq and bulk RNA-seq analyses, we identified SPHK1 served as a substrate for IGF2BP3 in an m6A-dependent manner. Further snRNA-seq, scRNA-seq, ST, and CODEX analysis revealed a closer topographical distance between IGF2BP3 + SPHK1 + bladder cancer cells and exhausted CD8 + T cells, providing one explanation for the superior response to immunotherapy in IGF2BP3 + SPHK1 + bladder cancer cells-enriched patients. Finally, an ICI-associated signature was developed based on the enriched genes of IGF2BP3 + SPHK1 + bladder cancer cells, and its potential ability to predict the response to immunotherapy was validated in two independent immunotherapy cohort. Conclusions Our study highlighted the critical involvement of the IGF2BP3/SPHK1 signaling in maintaining the stemness of CSCs and promoting MIBC progression. Additionally, these findings suggested that the IGF2BP3/SPHK1 signaling might serve as a biomarker for prognosis and immunotherapy response in MIBC.https://doi.org/10.1186/s12967-024-05685-8Muscle invasive bladder cancerCancer stem cellsIGF2BP3SPHK1Immunotherapy |
| spellingShingle | Yaobang Wang Wuyue Song Chao Feng Shulin Wu Zezu Qin Tao Liu Yu Ye Rong Huang Yuanliang Xie Zhong Tang Qiuyan Wang Tianyu Li Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer Journal of Translational Medicine Muscle invasive bladder cancer Cancer stem cells IGF2BP3 SPHK1 Immunotherapy |
| title | Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer |
| title_full | Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer |
| title_fullStr | Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer |
| title_full_unstemmed | Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer |
| title_short | Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer |
| title_sort | multi omics analysis unveils the predictive value of igf2bp3 sphk1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle invasive bladder cancer |
| topic | Muscle invasive bladder cancer Cancer stem cells IGF2BP3 SPHK1 Immunotherapy |
| url | https://doi.org/10.1186/s12967-024-05685-8 |
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