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Establishment of novel murine cell lines with defined mutations for preclinical in vitro and in vivo investigations of syngeneic epithelial ovarian cancer with different histological subtypes and inflammatory profiles

ABSTRACT: Preclinical modeling of epithelial ovarian cancer in immune competent mice progressing to spontaneous tumors is challenging, requiring multiple genetic modifications in the host. We have generated a total of 28 immortalized cell lines with distinct genetic traits. Primary OSE cells were propagated in vitro and reached immortalization after an average of 8-10 months in culture. The cells were further engineered via deletion of Trp53, activation of oncogenic KrasG12D, deletion of Pten tumor suppressor or KrasG12D/Pten-/- combination. Cellular transformation was confirmed in vivo, via orthotopic tumor growth syngeneic hosts. Two different Trp53 null cell lines recapitulate high grade serous histology, Pten deletion triggers aggressive, high grade endometrioid tumors, and cells with dual KrasG12D activation and Pten deletion model carcinosarcoma. The cells express different tumor antigens, secrete various levels of chemoattracting cytokines and chemokines and trigger diverse in vivo inflammation profiles, including intratumoral T and B lymphocyte conglomerates. RNAseq data from 16 cell lines reveal the gene expression profile of several distinct models for high grade serous, endometrioid and carcinosarcoma histotypes. This versatile collection of murine cell lines significantly broadens the preclinical modeling capacity in ovarian cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE232055 | GEO | 2023/07/01

REPOSITORIES: GEO

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Project description:Global gene expression patterns associated with early stage endometrial cancer have been reported, but changes in molecular expression associated with tumor grade, depth of myometrial invasion, and non-endometrioid histology have not been previously elucidated. Our group hypothesized there are unique genetic events underlying early endometrial carcinogenesis. Ninety-two samples of pathologically reviewed stage I endometrial cancers (80 endometrioid and 12 serous) with a heterogeneous distribution of grade and depth of myometrial invasion (i.e. 9 IAG1, 14 IAG2, 7 IAG3, 14 IBG1, 12 IBG2, 13 IBG3, 7 ICG1, 10 ICG2, and 6 ICG3) were examined in relation to 12 samples of atrophic endometrium from postmenopausal women. Specimens were analyzed using oligonucleotide microarray analysis and a subset of the differentially expressed transcripts was validated using quantitative PCR. Comparison of early stage cancers with normal endometrium samples by the univariate t-test with 10,000 permutations identified 900 genes that were differentially regulated by at least 4-fold at a p value of <0.001. Unsupervised analysis revealed that when compared to normal endometrium, serous and endometrioid stage I cancers appeared to have similar expression patterns. However, when compared in the absence of normal controls, they were distinct. Differential expression analysis revealed a number of transcripts that were common as well as unique to both histologic types. This data uncovers previously unrecognized, novel pathways involved in early stage endometrial cancers and identifys targets for prevention strategies that are inclusive of both endometrioid and serous histologic subtypes. Ninety-one samples of pathologically reviewed stage I endometrial cancers (79 endometrioid and 12 serous) with a heterogeneous distribution of grade and depth of myometrial invasion (i.e. 9 IAG1, 14 IAG2, 7 IAG3, 14 IBG1, 12 IBG2, 13 IBG3, 7 ICG1, 10 ICG2, and 6 ICG3) were examined in relation to 12 samples of atrophic endometrium from postmenopausal women. Specimens were analyzed using oligonucleotide array analysis.

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Establishment of novel murine cell lines with defined mutations for preclinical in vitro and in vivo investigations of syngeneic epithelial ovarian cancer with different histological subtypes and inflammatory profiles

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