Comparative analysis of syngeneic mouse models of high-grade serous ovarian cancer

Abstract

Ovarian cancers often exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate the heterogeneity of human disease are critical to develop new therapeutic approaches. While patient-derived models are a powerful tool for testing various therapeutics, their dependence on immune-compromised mice is severely limiting. Syngeneic mouse models, however, allow for the generation of tumours comprising the full repertoire of non-malignant cell types. Here we have performed a comparative analysis of diverse models of high-grade serous ovarian cancer based on transcriptomic profiling of 22 cell line models, and intrabursal and intraperitoneal tumours from 12 models. Among cell lines, we identify distinct features in signalling activity, such as elevated inflammatory signalling in STOSE and OVE16 models, and MAPK/ERK signalling in ID8 and OVE4 models; metabolic features, such as predicted reduction in glycolysis associated with subsets of engineered ID8 subclones; and relevant functional properties, including differences in EMT activation, PD-L1 and MHC class I expression, and predicted chemosensitivity. Finally, we evaluate variability in properties of the tumour microenvironment among models. We anticipate that this work will serve as a valuable resource, providing new insight to help in the selection of models for specific experimental objectives.

Heme oxygenase-1 expressing omental macrophages as a therapeutic target in ovarian high grade serous carcinoma

“…However, ID8, and other OSEderived models, such as STOSE 78 , can recapitulate the dominant features of HGSC, namely peritoneal dissemination and omental metastasis. However, it has been shown that different murine models represent the HGSC tumour microenvironment differently, as recently demonstrated 79 . For this reason, we attempted to replicate our findings using the fallopian-derived HGS2 line 24 .…”

BRCA1 and BRCA2 deficient tumour models generate distinct ovarian tumour microenvironments and differential responses to therapy

“…Despite an equivalent amount of DNA damage, the ID8 Trp53 −/− Brca2 −/− cells were the more olaparib-sensitive cell line, with viability reduced significantly at every dose of olaparib tested. Since olaparib differently affected Brcanull cell viability, the expression of genes associated with the PARP pathway in the ID8 cell lines was compared by querying RNA-seq data previously published in our lab [23]. We discovered that the ID8 Trp53 −/− Brca2 −/− cells growing in vitro demonstrated a higher expression of both PARP1 and PARP2 compared to the Brca1 −/− model (Fig.…”

“…As the TME analysis from the two models revealed differences in various cell populations and cytokines, we analyzed previously published bulk RNA sequencing data [23] from both Brca-deficient IP tumour models to further investigate the differences between them. The analysis revealed notable differences in the transcript levels of several cell type markers in Brca-null TMEs.…”

“…RNA-seq data from ID8 cell lines and IP tumours which were previously generated by the Vanderhyden lab [23] were used to assess transcriptomes related to PARP activity and differential TME gene expression. The cell lines were all of a similar passage number (< 20) and the IP tumours were collected at the humane endpoint.…”

“…C Heatmap presenting the expression levels of proteins involved in the PARP DNA repair pathway in the ID8 cell lines. RNA-seq data[23] collected from cell lines growing in vitro were analyzed to develop a normal distribution model of the expression of genes of interest. Each box represents the mean value of log-normalized RNA-seq data for 3 biological replicates.…”