单细胞RNA测序技术揭示卵巢高钙血症型小细胞癌复发病灶的细胞分子特征

doi:10.19401/j.cnki.1007-3639.2022.11.004

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (11): 1065-1073.doi: 10.19401/j.cnki.1007-3639.2022.11.004

单细胞RNA测序技术揭示卵巢高钙血症型小细胞癌复发病灶的细胞分子特征

康茗贻¹(), 郜意¹, 胥婧¹, 康玉¹(), 徐丛剑¹^,²^,³

1.复旦大学附属妇产科医院妇科，上海 200011
2.上海市女性生殖内分泌相关疾病重点实验室，上海 200011
3.复旦大学上海医学院妇产科学系，上海 200032

收稿日期:2022-10-20 修回日期:2022-11-17 出版日期:2022-11-30 发布日期:2022-12-14
通信作者: 康玉
作者简介:康茗贻（ORCID: 0000-0003-3469-1754），博士，住院医师。
基金资助:
上海申康医院发展中心临床科技创新项目(SHDC12020108);上海市老龄化和妇儿健康研究专项(2020YJZX0202)

Single-cell RNA sequencing reveals tissue architecture in small cell carcinoma of the ovary, hypercalcemic type

KANG Mingyi¹(), GAO Yi¹, XU Jing¹, KANG Yu¹(), XU Congjian¹^,²^,³

1. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
2. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
3. Department of Obstetrics and Gynecology of Shanghai Medical College, Fudan University, Shanghai 200032, China

Received:2022-10-20 Revised:2022-11-17 Published:2022-11-30 Online:2022-12-14
Contact: KANG Yu

摘要/Abstract

摘要：

背景与目的：卵巢高钙血症型小细胞癌（small cell carcinoma of the ovary, hypercalcemic type，SCCOHT）是高度恶性的、极为罕见的原发性未分化卵巢癌，本研究旨在分析SCCOHT肿瘤微环境及细胞分子特征，探究潜在药物靶标。方法：收集1例SCCOHT患者盆腔复发病灶，应用单细胞RNA测序（single-cell RNA sequencing，scRNA-seq）寻找关键细胞亚群及潜在药物靶点，进一步在细胞学层面进行验证。结果：SCCOHT复发病灶中有诱导性多能干细胞（induced pluripotent stem cell，iPSC）、神经施万细胞、神经上皮细胞和巨噬细胞4种细胞亚群和12个细胞亚簇。iPSCs细胞亚群显著上调的基因主要富集于细胞周期调控，其中PLK1基因上调最为显著。PLK1蛋白在SCCOHT组织切片中呈阳性表达，在SCCOHT细胞系中表达水平升高。结论：揭示了SCCOHT的肿瘤微环境由iPSC、神经施万细胞、神经上皮细胞及巨噬细胞组成，鉴定出iPSC关键细胞亚群，寻找到PLK1基因作为潜在的治疗靶点。

关键词: 卵巢高钙血症型小细胞癌, 单细胞RNA测序技术, PLK1

Abstract:

Background and purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly malignant, extremely rare primary undifferentiated ovarian cancer. This study aimed to reveal the tumor microenvironment and cellular and molecular characteristics of SCCOHT, and to explore potential drug targets. Methods: We collected recurrent pelvic lesions from one patient with SCCOHT, and applied single-cell RNA sequencing (scRNA-seq) to explore key cell subsets and potential drug targets. We further verified them at the cytological level. Results: There were four cell subsets and twelve cell subclusters of induced pluripotent stem cell (iPSC), neural Schwann cells, neuroepithelial cells and macrophages in the recurrent lesions of SCCOHT. The expression of genes significantly up-regulated by iPSC cell subgroups were mainly concentrated in cell cycle regulation, among which PLK1 was the most significantly up-regulated gene. PLK1 protein was positively expressed in SCCOHT tissue sections and increased in SCCOHT cell lines. Conclusion: It was revealed that the tumor microenvironment of SCCOHT was composed of iPSCs, neural Schwann cells, neuroepithelial cells and macrophages. The key cell subsets of iPSCs were identified, and PLK1 gene was found as a potential therapeutic target.

Key words: Small cell carcinoma of the ovary, hypercalcemic type, Single-cell RNA sequencing, PLK1

中图分类号:

R737.31

康茗贻, 郜意, 胥婧, 康玉, 徐丛剑. 单细胞RNA测序技术揭示卵巢高钙血症型小细胞癌复发病灶的细胞分子特征[J]. 中国癌症杂志, 2022, 32(11): 1065-1073.

KANG Mingyi, GAO Yi, XU Jing, KANG Yu, XU Congjian. Single-cell RNA sequencing reveals tissue architecture in small cell carcinoma of the ovary, hypercalcemic type[J]. China Oncology, 2022, 32(11): 1065-1073.

图/表 7

图1

图2

图3

图4

图5

图6

图7

参考文献 21

[1]	汪璟, 刘浏, 李可, 等. 卵巢高钙血症型小细胞癌研究进展[J]. 中国实用妇科与产科杂志, 2019, 35(10): 1166-70.
[2]	WANG J, LIU L, LI K, et al. Research progress of small cell carcinoma of ovary with hypercalcemia[J]. Chin J Pract Gynecol Obstet, 2019, 35(10): 1166-70.
[3]	YOUNG R H, OLIVA E, SCULLY R E. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases[J]. Am J Surg Pathol, 1994, 18(11): 1102-1116. pmid: 7943531
[4]	徐燕宁, 刘易欣, 陈凌. 卵巢高钙血症型小细胞癌的研究进展[J]. 国际妇产科学杂志, 2021, 48(5): 548-552.
[5]	XU Y N, LIU Y X, CHEN L. Advances in small cell carcinoma of the ovary-hypercalcemic type[J]. J Int Obstet Gynecol, 2021, 48(5): 548-552.
[6]	BELL E H, CHAKRABORTY A R, MO X K, et al. SMARCA4/BRG1 is a novel prognostic biomarker predictive of cisplatin-based chemotherapy outcomes in resected non-small cell lung cancer[J]. Clin Cancer Res, 2016, 22(10): 2396-2404. doi: 10.1158/1078-0432.CCR-15-1468 pmid: 26671993
[7]	TUMEH P C, HARVIEW C L, YEARLEY J H, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance[J]. Nature, 2014, 515(7528): 568-571. doi: 10.1038/nature13954
[8]	WANG Y M, CHEN S Y, COLBORNE S, et al. Histone deacetylase inhibitors synergize with catalytic inhibitors of EZH2 to exhibit antitumor activity in small cell carcinoma of the ovary, hypercalcemic type[J]. Mol Cancer Ther, 2018, 17(12): 2767-2779. doi: 10.1158/1535-7163.MCT-18-0348 pmid: 30232145
[9]	LANG J D, HENDRICKS W P D, ORLANDO K A, et al. Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multikinase inhibition[J]. Clin Cancer Res, 2018, 24(8): 1932-1943. doi: 10.1158/1078-0432.CCR-17-1928 pmid: 29440177
[10]	XUE Y B, MEEHAN B, MACDONALD E, et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary[J]. Nat Commun, 2019, 10: 558. doi: 10.1038/s41467-018-06958-9 pmid: 30718512
[11]	KARNEZIS A N, CHEN S Y, CHOW C, et al. Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines[J]. Gynecol Oncol, 2021, 160(2): 568-578. doi: 10.1016/j.ygyno.2020.12.004 pmid: 33328126
[12]	ANGERER P, HAGHVERDI L, BÜTTNER M, et al. Destiny: diffusion maps for large-scale single-cell data in R[J]. Bioinformatics, 2016, 32(8): 1241-1243. doi: 10.1093/bioinformatics/btv715 pmid: 26668002
[13]	LEVINE J H, SIMONDS E F, BENDALL S C, et al. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis[J]. Cell, 2015, 162(1): 184-197. doi: 10.1016/j.cell.2015.05.047 pmid: 26095251
[14]	BACAKOVA L, ZARUBOVA J, TRAVNICKOVA M, et al. Stem cells: their source, potency and use in regenerative therapies with focus on adipose-derived stem cells-a review[J]. Biotechnol Adv, 2018, 36(4): 1111-1126. doi: 10.1016/j.biotechadv.2018.03.011
[15]	OHNUKI M, TAKAHASHI K. Present and future challenges of induced pluripotent stem cells[J]. Philos Trans R Soc Lond B Biol Sci, 2015, 370(1680): 20140367. doi: 10.1098/rstb.2014.0367
[16]	WITKOWSKI L, CARROT-ZHANG J, ALBRECHT S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type[J]. Nat Genet, 2014, 46(5): 438-443. doi: 10.1038/ng.2931 pmid: 24658002
[17]	HARRISON M L, HOSKINS P, DU BOIS A, et al. Small cell of the ovary, hypercalcemic type: analysis of combined experience and recommendation for management. A GCIG study[J]. Gynecol Oncol, 2006, 100(2): 233-238. doi: 10.1016/j.ygyno.2005.10.024
[18]	JELINIC P, RICCA J, VAN OUDENHOVE E, et al. Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade[J]. J Natl Cancer Inst, 2018, 110(7): 787-790. doi: 10.1093/jnci/djx277 pmid: 29365144
[19]	NASSAR D, BLANPAIN C. Cancer stem cells: basic concepts and therapeutic implications[J]. Annu Rev Pathol, 2016, 11: 47-76. doi: 10.1146/annurev-pathol-012615-044438 pmid: 27193450
[20]	HAMANAKA R, MALOID S, SMITH M R, et al. Cloning and characterization of human and murine homologues of the drosophila polo serine-threonine kinase[J]. Cell Growth Differ, 1994, 5(3): 249-257. pmid: 8018557
[21]	TONG C, FAN H Y, LIAN L, et al. Polo-like kinase-1 is a pivotal regulator of microtubule assembly during mouse oocyte meiotic maturation, fertilization, and early embryonic mitosis[J]. Biol Reprod, 2002, 67(2): 546-554. doi: 10.1095/biolreprod67.2.546 pmid: 12135894

单细胞RNA测序技术揭示卵巢高钙血症型小细胞癌复发病灶的细胞分子特征

Single-cell RNA sequencing reveals tissue architecture in small cell carcinoma of the ovary, hypercalcemic type

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 7

参考文献 21

相关文章 1

编辑推荐

Metrics

本文评价