High-grade serous ovarian carcinoma organoids as models of chromosomal instability

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics.

Recurrent Somatic Copy Number Alterations and Their Association with Oncogene Expression Levels in High-Grade Ovarian Serous Carcinoma

“…We identified 11 known oncogenes with both amplification and overexpression in HGOSC. The findings related to PIK3CA, RAD21, RECQL4, and BRD4 align with prior studies, suggesting that overexpression of these genes is a result of amplification in HGOSC [22,[30][31][32]. To our knowledge, while overexpression due to amplification in genes such as TBL1XR1, PRKACA, and KRAS has not been linked specifically to HGOSC, it has been reported in other gynecological cancers [33][34][35].…”

Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors

“…Ovarian cancer is the most lethal gynecologic cancer, with a 5-year survival rate of less than 50 percent [2]. The tumor's biological properties, including increased invasiveness, chromosomal instability in cancer cells, and chemoresistance, are influenced by the tumor microenvironment, particularly cancer-associated fibroblasts, natural killer (NK) cells, and Th2 cells [14,35,38,39]. The response rate to the immunotherapy already developed and the survival outcomes in serous ovarian carcinomas depend on the immune cell composition in the tumor-associated microenvironment [41].…”

“…This can occur through the destabilization or inhibition of target mRNA translation, as well as the stabilization or activation of target mRNA translation [22,34]. Considering the proven genomic instability and alterations in the activity of numerous signaling pathways observed in cancer cells, particularly in serous ovarian carcinomas [15,[35][36][37][38][39], we conducted an analysis of piRNA expression profiles in SBT tissue from patients P13, P15, and P16 (Table 1), as well as in HGSOC tissue from patients P25, P26, and P28 (Table 1), in comparison to BSC tissue from patients P4, P6, and P7 (Table 1) using the deep sequencing method (Table S2, Sheet 1, and Sheet 2).…”

Advances and Challenges in Cancer Stem Cells for Onco-Therapeutics

“…3D culture systems can be derived from patient samples or established cancer cell lines [83][84][85]. For instance, patient-derived organoids in high-grade serous ovarian carcinoma have been successfully used to study different mutational processes driving chromosomal instability, such as homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication [86]. They can be used for testing compound sensitivity, and guide the development of precision therapeutics.…”