Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type
Abstract Purpose Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal cancer lacking effective treatment. Its genomic mutations and tumor microenvironment need further exploration. Methods We performed whole-exome sequencing or gene panel test to explore the SMARCA4 mu...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Journal of Ovarian Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13048-025-01649-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849744693705834496 |
|---|---|
| author | Yi Gao Kewei Zheng Haowen Tan Mingyi Kang Bingjian Lu Ling Chen Jing Xu Chong Lu Ranran Chai Congjian Xu Yu Kang |
| author_facet | Yi Gao Kewei Zheng Haowen Tan Mingyi Kang Bingjian Lu Ling Chen Jing Xu Chong Lu Ranran Chai Congjian Xu Yu Kang |
| author_sort | Yi Gao |
| collection | DOAJ |
| description | Abstract Purpose Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal cancer lacking effective treatment. Its genomic mutations and tumor microenvironment need further exploration. Methods We performed whole-exome sequencing or gene panel test to explore the SMARCA4 mutation spectrum in SCCOHT (15 samples). Single-cell RNA sequencing was conducted on one primary lesion with matched normal ovarian tissue and one recurrent lesion to investigate the intra-tumoral heterogeneity and immune microenvironment. Multiplex immunofluorescence staining validated T cell infiltration and PD-1 expression. Results 13/15 (86.7%) patients harbored SMARCA4 mutations. The loss of heterozygosity (LOH) occurred in 10/15 (66.7%) patients. Cancer cells and immune cells were observed in SCCOHT tumors. Cancer cells were further divided into seven subtypes and one from recurrent lesion exhibited the highest stemness accompanied by high expression of genes related to cell mitosis (AURKB, CHEK2, CCNB1, WEE1), DNA repair (BRCA1, RAD51) and epigenetic (EZH2, DNMT1). Immune cells mainly included macrophages and T cells. Lipid-associated tumor-associated macrophages (TAMs) was mainly in primary lesion while inflammatory cytokine-enriched TAMs in recurrent lesion. CD4 +/ CD8 + T cell infiltration was observed in SCCOHT tumor and a certain proportion of T cells expressed PD-1. Conclusions SCCOHT exhibits universal SMARCA4 LOH and significant intra-tumoral heterogeneity, suggesting potential therapeutic targets, including CHEK2, CCNB1, and WEE1. Exhausted T cells and distinct TAM subsets infiltrate tumors. Targeting macrophage polarization or cytokine signaling may also be promising. These findings provide insights for developing novel therapies to improve outcomes in SCCOHT. Clinical trial number Not applicable. |
| format | Article |
| id | doaj-art-81f9a2293bdb4301a32c7b7dcb92141f |
| institution | DOAJ |
| issn | 1757-2215 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Ovarian Research |
| spelling | doaj-art-81f9a2293bdb4301a32c7b7dcb92141f2025-08-20T03:10:13ZengBMCJournal of Ovarian Research1757-22152025-04-0118111210.1186/s13048-025-01649-8Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic typeYi Gao0Kewei Zheng1Haowen Tan2Mingyi Kang3Bingjian Lu4Ling Chen5Jing Xu6Chong Lu7Ranran Chai8Congjian Xu9Yu Kang10Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversitySynerGeneDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityDepartment of Surgical Pathology, School of Medicine, Women’s Hospital, Zhejiang UniversityDepartment of Pathology, Tianjin Central Hospital of Gynecology ObstetricsDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityDepartment of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityAbstract Purpose Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal cancer lacking effective treatment. Its genomic mutations and tumor microenvironment need further exploration. Methods We performed whole-exome sequencing or gene panel test to explore the SMARCA4 mutation spectrum in SCCOHT (15 samples). Single-cell RNA sequencing was conducted on one primary lesion with matched normal ovarian tissue and one recurrent lesion to investigate the intra-tumoral heterogeneity and immune microenvironment. Multiplex immunofluorescence staining validated T cell infiltration and PD-1 expression. Results 13/15 (86.7%) patients harbored SMARCA4 mutations. The loss of heterozygosity (LOH) occurred in 10/15 (66.7%) patients. Cancer cells and immune cells were observed in SCCOHT tumors. Cancer cells were further divided into seven subtypes and one from recurrent lesion exhibited the highest stemness accompanied by high expression of genes related to cell mitosis (AURKB, CHEK2, CCNB1, WEE1), DNA repair (BRCA1, RAD51) and epigenetic (EZH2, DNMT1). Immune cells mainly included macrophages and T cells. Lipid-associated tumor-associated macrophages (TAMs) was mainly in primary lesion while inflammatory cytokine-enriched TAMs in recurrent lesion. CD4 +/ CD8 + T cell infiltration was observed in SCCOHT tumor and a certain proportion of T cells expressed PD-1. Conclusions SCCOHT exhibits universal SMARCA4 LOH and significant intra-tumoral heterogeneity, suggesting potential therapeutic targets, including CHEK2, CCNB1, and WEE1. Exhausted T cells and distinct TAM subsets infiltrate tumors. Targeting macrophage polarization or cytokine signaling may also be promising. These findings provide insights for developing novel therapies to improve outcomes in SCCOHT. Clinical trial number Not applicable.https://doi.org/10.1186/s13048-025-01649-8SMARCA4SCCOHTIntra-tumoral heterogeneityImmune microenvironment |
| spellingShingle | Yi Gao Kewei Zheng Haowen Tan Mingyi Kang Bingjian Lu Ling Chen Jing Xu Chong Lu Ranran Chai Congjian Xu Yu Kang Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type Journal of Ovarian Research SMARCA4 SCCOHT Intra-tumoral heterogeneity Immune microenvironment |
| title | Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type |
| title_full | Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type |
| title_fullStr | Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type |
| title_full_unstemmed | Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type |
| title_short | Single-cell RNA sequencing reveals the intra-tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary, hypercalcemic type |
| title_sort | single cell rna sequencing reveals the intra tumoral heterogeneity and immune microenvironment of small cell carcinoma of the ovary hypercalcemic type |
| topic | SMARCA4 SCCOHT Intra-tumoral heterogeneity Immune microenvironment |
| url | https://doi.org/10.1186/s13048-025-01649-8 |
| work_keys_str_mv | AT yigao singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT keweizheng singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT haowentan singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT mingyikang singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT bingjianlu singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT lingchen singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT jingxu singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT chonglu singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT ranranchai singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT congjianxu singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype AT yukang singlecellrnasequencingrevealstheintratumoralheterogeneityandimmunemicroenvironmentofsmallcellcarcinomaoftheovaryhypercalcemictype |