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Patient-Derived Tumor Xenografts Plus Ex Vivo Models Enable Drug Validation for Tenosynovial Giant Cell Tumors

  • Translational Research
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Tenosynovial giant cell tumor (TGCT) is a locally aggressive tumor with colony-stimulating factor 1 receptor (CSF1R) signal expression. However, there is a lack of better in vivo and ex vivo models for TGCT. This study aims to establish a favorable preclinical translational platform, which would enable the validation of efficient and personalized therapeutic candidates for TGCT.

Patients and Methods

Histological analyses were performed for the included patients. Fresh TGCT tumors were collected and sliced into 1.0–3.0 mm3 sections using a sterilized razor blade. The tumor grafts were surgically implanted into subrenal capsules of athymic mice to establish patient-derived tumor xenograft (PDTX) mouse models. Histological and response patterns to CSF1R inhibitors evaluations were analyzed. In addition, ex vivo cultures of patient-derived explants (PDEs) with endpoint analysis were used to validate TGCT graft response patterns to CSF1R inhibitors.

Results

The TGCT tumor grafts that were implanted into athymic mice subrenal capsules maintained their original morphological and histological features. The “take” rate of this model was 95% (19/20). Administration of CSF1R inhibitors (PLX3397, and a novel candidate, WXFL11420306) to TGCT-PDTX mice was shown to reduce tumor size while inducing intratumoral apoptosis. In addition, the CSF1R inhibitors suppressed circulating nonspecific monocyte levels and CD163-positive cells within tumors. These response patterns of engrafts to PDTX were validated by ex vivo PDE cultures.

Conclusions

Subrenal capsule supports the growth of TGCT tumor grafts, maintaining their original morphology and histology. This TGCT-PDTX model plus ex vivo explant cultures is a potential preclinical translational platform for locally aggressive tumors, such as TGCT.

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Acknowledgment

This work is supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 2018ZX09733001, China), the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China (No. 2019JDJQ008), the Key Programs of Sichuan Scientific Committee Grant in China (No.2020YFS0144), the Special Program of China Postdoctoral Science Foundation (No. 2020T130447), and the National Natural Science Foundation of China (No. 82002847).

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Authors and Affiliations

  1. Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China

    Fan Tang MD, PhD, Li Min MD, PhD, Yong Zhou MD, PhD, Yi Luo MD & Chong-Qi Tu MD

  2. Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China

    Fan Tang MD, PhD, Wei-Qi Hong PhD, Si-Yuan Chen PhD, Jing-Yun Yang PhD, Hou-Hui Shi MD & Xia-Wei Wei PhD

  3. Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Yan Tie MD, PhD

  4. Department of Pathology, West China Hospital, Sichuan University, Chengdu, China

    Xin He MD

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  1. Fan Tang MD, PhD
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Tang, F., Tie, Y., Hong, WQ. et al. Patient-Derived Tumor Xenografts Plus Ex Vivo Models Enable Drug Validation for Tenosynovial Giant Cell Tumors. Ann Surg Oncol 28, 6453–6463 (2021). https://doi.org/10.1245/s10434-021-09836-9

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