A Genomically Characterized Collection of High-Grade Serous Ovarian Cancer Xenografts for Preclinical Testing

Cybulska, Paulina; Stewart, Jocelyn M.; Sayad, Azin; Virtanen, Carl; Shaw, Patricia; Clarke, Blaise A.; Stickle, Natalie; Bernardini, Marcus Q.; Neel, Benjamin G.

doi:10.1016/j.ajpath.2018.01.019

Cited by 25 publications

(26 citation statements)

References 55 publications

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“…In analyzing the gene mutation of ovarian cancer, one research group established HGS-OC PDXs and reported a similar copy number variation to original tumor, and that the frequency of TP53 alterations in PDXs was 93%, BRCA1 mutation was 13%, BRCA2 mutation was 8%, consistent with the analysis in The Cancer Genome Atlas (TCGA) data [49]. Similarly, another study indicated that the rate of TP53 mutations in ten HGS-OC PDXs was 100%, BRCA1 mutation with methylation was 20%, and BRCA2 mutation was 30% [40].…”

Section: Gene Expressionsupporting

confidence: 61%

The Application of Patient-Derived Xenograft Models in Gynecologic Cancers

et al. 2020

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Recently, due to the limitations of cell line models and animal models in the preclinical research with insufficient reflecting the physiological situation of humans, patient-derived xenograft (PDX) models of many cancers have been widely developed because of their better representation of the tumor heterogeneity and tumor microenvironment with retention of the cellular complexity, cytogenetics, and stromal architecture. PDX models now have been identified as a powerful tool for determining cancer characteristics, developing new treatment, and predicting drug efficacy. An increase in attempts to generate PDX models in gynecologic cancers has emerged in recent years to understand tumorigenesis. Hence, this review summarized the generation of PDX models and engraftment success of PDX models in gynecologic cancers. Furthermore, we illustrated the similarity between PDX model and original tumor, and described preclinical utilization of PDX models in gynecologic cancers. It would help supply better personalized therapy for gynecologic cancer patients.

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Section: Gene Expressionsupporting

confidence: 61%

The Application of Patient-Derived Xenograft Models in Gynecologic Cancers

et al. 2020

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“…We previously found that primary human HGSOC cells implanted into the mouse mammary fat pad (MFP) recapitulate HGSOC histomorphology, inter- and intra-tumor heterogeneity, and patient drug response (49,50). Therefore, as an initial test of their tumor-forming capacity, we injected wild type and mutant organoids into the MFPs of nu/nu mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

Neel

Zhang

et al. 2018

Preprint

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The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response. SIGNIFICANCE The cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.

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“…Thus, the goal of this study is to identify driver and therapeutically actionable molecular alterations in ovarian cancer. Primarily, with this purpose in mind, we [11] and other groups [12][13][14][15][16][17][18] have developed platforms of Patient-Derived Xenografts (PDXs) of EOC that can recapitulate the tumour biology and clinical responses observed in donor patients. PDXs provide the most conclusive tool to validate low frequency mutations as biomarkers for targeted therapy, as evidenced by the use of colorectal cancer PDX models to predict successful clinical trials [19].…”

Section: Introductionmentioning

confidence: 99%

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

D'Ambrosio

Erriquez

Arigoni

et al. 2020

Cells

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Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.

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A Genomically Characterized Collection of High-Grade Serous Ovarian Cancer Xenografts for Preclinical Testing

Cited by 25 publications

References 55 publications

The Application of Patient-Derived Xenograft Models in Gynecologic Cancers

The Application of Patient-Derived Xenograft Models in Gynecologic Cancers

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

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