Establishment and characterization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma

Elien De Thaye,Joachim Taminau,Wim Ceelen,Hannelore Denys,Olivier De Wever,Joni Van Der Meulen,Jo Van Dorpe,Geert Berx,Jan Van Bocxlaer,Glenn Wagemans,Koen Van De Vijver

doi:10.1038/s41598-020-63738-6

Elien De Thaye, Joachim Taminau + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-63738-6

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Abstract

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Novel treatment options are urgently needed to improve patient outcome. Clinically relevant cell lines and patient-derived xenograft (PDX) models are of critical importance to therapeutic regimen evaluation. Here, a PDX model was established, by orthotopic engraftment after subperitoneal tumor slurry injection of low-grade SOC, resulting in an early-stage transplantable peritoneal metastasis (PM)-PDX model. Histology confirmed the micropapillary and cribriform growth pattern with intraluminal tumor budding and positivity for PAX8 and WT1. PM-PDX dissociated cells show an epithelial morphotype with a 42 h doubling time and 40% colony forming efficiency, they are low sensitive to platinum derivatives and highly sensitive to paclitaxel (IC50: 6.3 ± 2.2 nM, mean ± SEM). The patient primary tumor, PM, PM-PDX and derived cell line all show a KRAS c.35 G > T (p.(Gly12Val)) mutation and show sensitivity to the MEK inhibitor trametinib in vitro (IC50: 7.2 ± 0.5 nM, mean ± SEM) and in the PM mouse model. These preclinical models closely reflecting patient tumors are useful to further elucidate LGSOC disease progression, therapy response and resistance mechanisms.

Highlights

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy
We confirmed the histological features of the early-stage patient-derived xenograft (PDX) such as micropapillae surrounded by stroma in the first passage and marked architectural complexity in the second passage most probably due to anastomosis of micropapillae forming the elongated and branching structures
The genomic aberration characterized by KRAS mutation is consistent in the peritoneal metastasis (PM)-PDX and PM-Low-grade serous ovarian carcinoma (LGSOC)-01 cell line

Summary

Introduction

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Tumor xenografts can grow orthotopically into the corresponding anatomic region but their use is often hindered by a need for a high level of technical skills, time and cost[15] For some cancers, such as colorectal, breast, lung, pancreatic, head and neck, melanoma, gastric, ovarian, prostate and renal cancer, methodologies for PDX establishment and characterization are already described in literature with engraftment rates ranging from 9 to 90% of success[14,16]. For the first time, an orthotopic PDX model, based on a subperitoneal tumor slurry injection, and cancer cell line from a peritoneal metastasis of LGSOC were established This model showed a KRAS mutation and sensitivity to the MEK inhibitor trametinib demonstrating its clinical relevance to study treatment responsiveness and resistance mechanisms

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