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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

Summary

The present protocol establishes and characterizes a patient-derived xenograft (PDX) model of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), as PDX models are rapidly becoming the standard in the field of translational oncology.

Abstract

Patient-derived xenograft (PDX) models faithfully preserve the histological and genetic characteristics of the primary tumor and maintain its heterogeneity. Pharmacodynamic results based on PDX models are highly correlated with clinical practice. Anaplastic thyroid carcinoma (ATC) is the most malignant subtype of thyroid cancer, with strong invasiveness, poor prognosis, and limited treatment. Although the incidence rate of ATC accounts for only 2%-5% of thyroid cancer, its mortality rate is as high as 15%-50%. Head and neck squamous cell carcinoma (HNSCC) is one of the most common head and neck malignancies, with over 600,000 new cases worldwide each year. Herein, detailed protocols are presented to establish PDX models of ATC and HNSCC. In this work, the key factors influencing the success rate of model construction were analyzed, and the histopathological features were compared between the PDX model and the primary tumor. Furthermore, the clinical relevance of the model was validated by evaluating the in vivo therapeutic efficacy of representative clinically used drugs in the successfully constructed PDX models.

Introduction

The PDX model is an animal model in which human tumor tissue is transplanted into immunodeficient mice and grows in the environment provided by the mice1. Traditional tumor cell line models suffer from several disadvantages, such as the lack of heterogeneity, the inability to retain the tumor microenvironment, the vulnerability to genetic variations during repeated in vitro passages, and the poor clinical application2,3. The main drawbacks of genetically engineered animal models are the potential loss of the genomic features of human tumors, the introduction of new unknown mutations, and the difficulty in identifying the degree of homology between mouse tumors and human tumors4. In addition, the preparation of genetically engineered animal models is expensive, time-consuming, and relatively inefficient4.

The PDX model has many advantages over other tumor models in terms of reflecting tumor heterogeneity. From the perspective of histopathology, although the mouse counterpart replaces the human stroma over time, the PDX model preserves the morphological structure of the primary tumor well. In addition, the PDX model conserves the metabolomic identity of the primary tumor for at least four generations and better reflects the complex inter-relationships between tumor cells and their microenvironment, making it unique in simulating the growth, metastasis, angiogenesis, and immunosuppression of human tumor tissue5,6,7. At the cellular and molecular levels, the PDX model accurately reflects the inter- and intra-tumor heterogeneity of human tumors, as well as the phenotypic and molecular characteristics of original cancer, including gene expression patterns, mutation status, copy number, and DNA methylation and proteomics8,9. PDX models with different passages have the same sensitivity to drug therapy, indicating that the gene expression of PDX models is highly stable10,11. Studies have shown an excellent correlation between the response of the PDX model to a drug and the clinical responses of patients to that drug12,13. Therefore, the PDX model has emerged as a powerful preclinical and translational research model, particularly for drug screening and clinical prognosis prediction.

Thyroid cancer is a common malignant tumor of the endocrine system and is a human malignancy that has shown a rapid increase in incidence in recent years14. Anaplastic thyroid carcinoma (ATC) is the most malignant thyroid cancer, with a median patient survival of only 4.8 months15. Although only a minority of thyroid cancer patients are diagnosed with ATC each year in China, the mortality rate is close to 100%16,17,18. ATC usually grows rapidly and invades the adjacent tissues of the neck as well as the cervical lymph nodes, and about half of the patients have distant metastases19,20. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world and one of the leading causes of cancer deaths, with an estimated 600,000 people suffering from HNSCC each year21,22,23. HNSCC includes a large number of tumors, including those in the nose, sinuses, mouth, tonsils, pharynx, and larynx24. ATC and HNSCC are two of the main head and neck malignancies. In order to facilitate the development of novel therapeutic agents and personalized treatments, it is necessary to develop robust and advanced preclinical animal models such as PDX models of ATC and HNSCC.

This article introduces detailed methods for establishing the subcutaneous PDX model of ATC and HNSCC, analyzes the key factors affecting the tumor take rate in model construction, and compares the histopathological characteristics between the PDX model and the primary tumor. Meanwhile, in this work, in vivo pharmacodynamic tests were performed using the successfully constructed PDX models in order to validate their clinical relevance.

Protocol

All the animal experiments were performed in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care guidelines and protocols approved by the Institutional Animal Care and Use Committee of West China Hospital, Sichuan University. NOD-SCID immunodeficient mice aged 4-6 weeks old (of both sexes) and female Balb/c nude mice aged 4-6 weeks old were used for the present study. The animals were obtained from a commercial source (see Table of Materials). The ethics committee of West China Hospital authorized the study with human subjects (protocol number 2020353). Each patient provided written informed consent.

1. Experimental preparation

  1. Arrange disposable blades, sterilized scissors and tweezers, and other instruments required for tumor transplantation, place them on the ultra-clean workbench, and irradiate them with ultraviolet light in advance.
  2. Prepare sterile saline and Petri dishes for use during the test.

2. Acquisition and transport of fresh tumor tissue

  1. Obtain fresh tumor samples (usually larger than 5 mm x 5 mm in size) from the operating room, and place them in a 15 mL or 50 mL centrifuge tube containing sterile HTK solution (see Table of Materials) or saline. Label the centrifuge tubes.
    NOTE: Fresh tumor samples were obtained by surgical removal or puncture from patients with ATC or HNSCC.
  2. Put the centrifuge tubes in an ice box prepared in advance.
    NOTE: During this time, the transplant operator must prepare the necessary items for transplantation (see Table of Materials).
  3. Ensure that the time between sample collection and transportation to the laboratory for PDX construction does not exceed 2 h. During transport, surround the tubes containing the tissues with an ice-water mixture or ice packs to preserve the tissue activity.

3. Tumor transplantation

  1. Once the tumor tissues arrive at the laboratory, record and renumber them.
    NOTE: For the present study, the patient information was kept strictly confidential. The remaining steps of the procedure were performed in a biosafety level 2 (BSL-2) laboratory. When entering the laboratory, wearing a smock over the work clothes or protective clothing, a hat, and a mask is recommended. The treatment of tumor tissue is conducted in a biosafety cabinet.
  2. Disinfect the centrifuge tubes containing the tumor tissues with 75% alcohol, and place them on the operating table. Transfer the tumor tissues to 6 cm Petri dishes filled with saline using sterilized ophthalmic forceps. Next, cut them into small pieces of about 2 mm x 2 mm and 3 mm x 3 mm using a blade.
  3. Transfer the pieces of tumor tissues into a 6 cm Petri dish containing the appropriate amount of saline, wrap the dish with the sealing film, place it in an ice box, and carry it into the specific pathogen-free (SPF) animal room along with the necessary instruments (a pair of scissors, forceps, and inoculation needles).
  4. Prepare the animal following the steps below.
    1. Remove the hair on the right lateral thorax of 4-6 week-old female or male NOD-SCID immunodeficient mice, and disinfect the skin with 75% alcohol. Anesthetize the mice by an intraperitoneal injection of 80 mg/kg ketamine and 10 mg/kg xylazine (see Table of Materials), and smear their eyes with vet ointment to prevent dryness. Confirm anesthesia depth via loss of pedal reflex.
    2. Make a 2 mm incision with scissors through the skin at the middle of the right lateral thorax of mice.
  5. Take a tumor piece from the Petri dish, and place it into the 2.4 mm x 2.0 mm trocar needle (see Table of Materials) with forceps.
  6. Hold the mouse, tighten the skin at the puncture site, use the trocar containing the tumor pieces to insert the tumor through the initial 2 mm skin incision, move to the back of the shoulder, and push the trocar core.
  7. Ensure that the tumor piece is pushed out and is left in the transitional sinus formed by the trocar puncture, and then pull out the trocar.
  8. If the tumor moves with the needle when it is withdrawn, use the trocar to reset it and suture the incision.
    NOTE: In this study, each mouse was inoculated at the dorsal fore and hind limbs. One to three mice were inoculated per tumor sample from each patient based on the tumor size.

4. Tumor tissue preservation, fixation, and protein freezing

NOTE: The remaining tumor tissues were used for seed preservation, fixation, and DNA/RNA/protein freezing, respectively.

  1. Remove the saline from the tumor surface with a sterile gauze before placing it in the cryopreservation tube to ensure that the tumor surface is not excessively wet.
  2. Put four to six pieces of 2 mm x 2 mm tumor tissue in a 2 mL cell cryopreservation tube, add 1 mL of cryopreservation solution composed of 90% fetal bovine serum (FBS) and 10% dimethyl sulfoxide (DMSO) into the tube, put the tube in a gradient cooling box, freeze it at −80 °C overnight, and finally, transfer it to liquid nitrogen.
  3. Place the 3 mm x 3 mm tumor tissue blocks in 10% buffered formalin for tissue fixation for pathological examination.
  4. Put the 3 mm x 3 mm tissue block into a 2 mL cell cryopreservation tube, quickly freeze it in liquid nitrogen, and then transfer to a −80 °C refrigerator for DNA/RNA and protein extraction.
  5. Collect the clinical information of the patients, such as the smoking history, tumor size, differentiation, pathological subtype, cancer grade, cancer stage, distant metastasis, origin, medical history, immunohistochemistry, human papillomavirus (HPV) infection in HNSCC patients, and treatment medication.

5. Passaging, cryopreservation, and resuscitation of PDX model tumors

  1. Measure the length and width of the subcutaneous tumors in mice by using vernier calipers once a week, and calculate the tumor volume according to the formula: tumor volume = 0.5 × length × width2. Draw the tumor growth curve.
  2. When the PDX tumor reaches 2,000 mm3, passage it to the next generation of mice, and perform tumor re-transplantation. Perform the preparation of the instruments following step 4.
  3. Euthanize the mice by cervical dislocation after anesthetizing with 80 mg/kg ketamine.
  4. Disinfect the skin with 75% alcohol. Then, cut the skin surrounding the tumor using scissors, then remove the tumor with forceps, and place it in a Petri dish. 
  5. Perform the tumor transplantation procedure following step 3.
  6. Perform the preservation and cryopreservation of the PDX model tumors following step 4.
  7. For the resuscitation of the tumor tissue, follow the principle of slow freezing and quick dissolving. After taking out the cryovials from liquid nitrogen, quickly place them in a water bath at 37 °C for rapid dissolving.
  8. Gently shake the cryovials in the water bath to accelerate the thawing process.
  9. Thaw, transfer the tumor pieces to the prepared normal saline for washing, and then inoculate the next generation of mice. For the specific operation, please see the tissue transplantation procedure in step 3.

6. Determining the therapeutic efficacy of lenvatinib and cisplatin in the ATC PDX model

NOTE: The ATC PDX model was used to test the therapeutic effect of the tyrosine kinase inhibitor lenvatinib and the chemotherapeutic drug cisplatin25,26,27.

  1. Select the P5 generation tumor tissue of an ATC PDX model (THY-017), cut into 2-4 mm3 tissue pieces, and inoculate subcutaneously (step 3) to the right back of ten 4-6 week female Balb/c nude mice.
  2. Select 15 mice with tumor volumes between 50-150 mm3, and divide them into three groups.
  3. Administer lenvatinib (10 mg/kg) intragastrically to one group once daily for 15 days, administer cisplatin (3 mg/kg) intraperitoneally to one group every 3 days for a total of six doses, and administer the control group with the same volume of normal saline.
  4. Measure the body weight and tumor volume of the mice twice per week.
  5. At the end of the test, euthanize the mice (step 5.3), and weigh the tumors.

Results

A total of 18 thyroid cancer specimens were transplanted, and five PDX models of thyroid cancer were successfully constructed (27.8% tumor take rate), including four cases of undifferentiated thyroid cancers and one case of anaplastic thyroid cancer. The correlation between the success rate of model construction and the age, gender, tumor diameter, tumor grade, and differentiation were analyzed. Although the model success rate of grade 4 tumor samples was higher than for samples with lower grades, and the success rate of...

Discussion

This study has successfully established the subcutaneous PDX models of ATC and HNSCC. There are many aspects to pay attention to during the process of PDX model construction. When the tumor tissue is separated from the patient, it should be put into the ice box and sent to the laboratory for inoculation as soon as possible. After the tumor arrives at the laboratory, the operator must pay attention to maintaining a sterile field and practice aseptic procedures. For needle biopsy samples, because the tumor tissue is partic...

Disclosures

No potential conflicts of interest are disclosed.

Acknowledgements

This work was supported by the Sichuan Province Science and Technology Support Program (Grant Nos. 2019JDRC0019 and 2021ZYD0097), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYJC18026), the 1.3.5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (Grant No. 2020HXFH023), the Fundamental Research Funds for the Central Universities (SCU2022D025), the International Cooperation Project of Chengdu Science and Technology Bureau (Grant No. 2022-GH02-00023-HZ), the Innovation Spark Project of Sichuan University (Grant No. 2019SCUH0015), and the Talent Training Fund for Medical-engineering Integration of West China Hospital - University of Electronic Science and Technology (Grant No. HXDZ22012).

Materials

NameCompanyCatalog NumberComments
2.4 mm x 2.0 mm trocarShenzhen Huayang Biotechnology Co., Ltd18-9065
Balb/c nude miceBeijing Vital River Laboratory Animal Technology Co., Ltd.401
Biosafety cabinetSuzhou AntaiBSC-1300IIA2
BladeShenzhen Huayang Biotechnology Co., Ltd18-0823
Centrifuge tube Corning430791/430829
Cryopreservation tubeChengdu Dianrui Experimental Instrument Co., Ltd/
Custodiol HTK-SolutionCustodiol2103417
Dimethyl sulfoxide(DMSO)SIGMA-ALORICHD5879-500mL
Electronic balanceMETTLERME104
Electronic digital caliperChengdu Chengliang Tool Group Co., Ltd0-220
fetal bovine serum(FBS)VivaCellC04001-500
IBM SPSS Statistics 26IBM
KetamineJiangsu Zhongmu Beikang Pharmaceutical Co., Ltd 100761663
LenvatinibApexBioA2174
NOD SCID immunodeficient miceBeijing Vital River Laboratory Animal Technology Co., Ltd.406
Pen-Strep SolutionBiological Industries03-03101BCS
Petri dishWHBWHB-60/WHB-100
Saline Sichuan KelunW220051705
ScissorShenzhen Huayang Biotechnology Co., Ltd18-0110
TweezerShenzhen Huayang Biotechnology Co., Ltd18-1241
Vet ointmentPfizer Inc.P10015353
XylazineDunhua Shengda Animal Medicine Co., Ltd070031777

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