Spontaneous Murine Model of Anaplastic Thyroid Cancer
February 3rd, 2023
Here, we present a standard pipeline to obtain murine ATC tumors by spontaneous genetically engineered mouse models. Further, we present tumor dynamics and pathological information about the primary and metastasized lesions. This model will help researchers to understand tumorigenesis and facilitate drug discoveries.
We present a standard pipeline to obtain MATC tumors and present tumor dynamics and pathological information. This module will help researchers to understand tumor oncogenesis and facilitate drug discoveries. The MATC facilitates the collection of MATC samples in the whole tumor oncogenesis course, and each is a spontaneous mirror model, with the complete immune system and immune microenvironment.
MATC can be used to study the effects of specific gene functions on ATC, understand the mechanisms of thyroid tumor progression, and ultimately improve the prognosis of ATC patients. To begin, weigh tamoxifen and dissolve it in 15 milliliters of corn oil by ultrasound at a concentration of 20 milligrams per milliliter. Then store it in a brown container at four degrees Celsius.
At around eight weeks, weigh the mice with electronic scales and then administer tamoxifen intraperitoneally twice at an interval of one week. After preparing the dissection tools and mouse-tissue fixing solution, fill a clean 10 centimeter dish with about 10 milliliters of sterile PBS for temporary tissue storage, and for washing off the blood from the tissue surface. For thyroid extraction, place the euthanized mouse on the dissecting board.
After disinfecting the neck area, use sterile scissors and forceps. Make a small incision above the center of the clavicle and continue at midline up to the mouth. Locate the submandibular gland and remove it to expose the anatomical location of the thyroid, which is near the thyroid cartilage and trachea.
Once the thyroid gland is located, carefully dissected from the rest of the neck region using sterile scissors, and put it in the previously prepared dish containing sterile PBS. Remove the blood from the surface of the thyroid tissue, and with sterile scissors, carefully cut off the trachea. Then put the thyroid tissue on the sterile cloth and measure the size of the left and right lobes of the thyroid gland using Vernier calipers.
Using a sterile blade, divide the left and right lobes of the thyroid gland into two parts. Put one part into two milliliters of 4%paraformaldehyde solution for fixation and another into liquid nitrogen for preservation. For extracting the lung and liver, pinch just above the mouse's penis after disinfecting the the area.
Then make a small incision and cut along the midline of the abdomen to the subclavian bone. Expose the abdominal cavity. After locating the liver in the upper part of the abdomen, carefully remove it and place it into a new dish containing sterile PBS.
Grossly observe and count the metastasis in the lung and liver, followed by obtaining a picture. With a sterile blade, divide the lung and liver tissues into two parts. As demonstrated previously, fix one part and preserve the other part in liquid nitrogen.
The tumor growth curve was plotted to observe the dynamic alteration of the tumor size. The tumors grew slowly in the early stage, and became dramatically faster in the late stage. On the other hand, a survival curve was plotted based on recorded survival time.
The median survival of MATC was 130 days. In addition, approximately 92%lung metastasis was found in most MATC. In the HE staining of the primary tumors and metastatic lung tissues of MATC, the one month inducible tissues showed incomplete solidified features and the coexistence of follicular structures and malignant cells, whereas the thyroid follicular structures disappeared and the tumor solidified completely after a two month induction.
The primary tumor revealed that the tumor cells were morphologically diverse, with pleomorphic giant cells and spindle-shaped cells. Furthermore, the HE staining of metastatic lung tissues showed that the normal lung tissue was a reticular structure with clear alveolar structures and airspaces. Nevertheless, lung metastases showed a loss of normal reticular structure, air cavity thickening, and lung parenchyma.
Meanwhile, the immunohistochemical staining of MATC tumor with different antibodies showed highly proliferative tumor cells, lymphocyte infiltration, an extensive infiltration of myeloid cells, which was consistent with clinical samples. During dissection, the anatomical location of the thyroid gland needs to be correctly understood. The thyroid gland is placed near the thyroid cartilage and the trachea.
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Overview
This article presents a standard pipeline for obtaining murine ATC tumors using genetically engineered mouse models. It details tumor dynamics and pathological information, aiding researchers in understanding tumorigenesis and facilitating drug discoveries.
Key Study Components
Area of Science
- Oncology
- Genetics
- Pathology
Background
- ATC (Anaplastic Thyroid Carcinoma) is a highly aggressive cancer.
- Understanding tumor dynamics is crucial for developing effective treatments.
- Genetically engineered mouse models provide insights into tumorigenesis.
- The immune microenvironment plays a significant role in tumor progression.
Purpose of Study
- To establish a reliable method for generating ATC tumors in mice.
- To analyze tumor dynamics and pathology of primary and metastatic lesions.
- To facilitate research on drug discovery and therapeutic strategies.
Methods Used
- Use of genetically engineered mouse models to induce ATC tumors.
- Collection of tumor samples throughout the oncogenesis process.
- Analysis of tumor dynamics and immune microenvironment interactions.
- Application of tamoxifen for tumor induction in mice.
Main Results
- Successful establishment of a murine model for studying ATC.
- Detailed characterization of tumor dynamics and pathology.
- Insights into the role of specific genes in thyroid tumor progression.
- Potential for improving prognosis in ATC patients through research findings.
Conclusions
- The developed model is a valuable tool for studying ATC.
- Findings contribute to understanding tumorigenesis and treatment strategies.
- Future research can leverage this model for drug discovery efforts.
Frequently Asked Questions
Executive Industry Relevance
The spontaneous murine model of anaplastic thyroid cancer (mATC) provides a unified, genetically defined system for interrogating ATC tumorigenesis and immune microenvironment dynamics. This model addresses the scarcity and heterogeneity of clinical ATC samples, enabling robust mechanistic de-risking and translational continuity for preclinical drug discovery. Its high pathophysiological similarity to human ATC supports predictive confidence in early-stage therapeutic hypothesis testing and portfolio triage.
Strategic Applications in Biopharma R&D
Early Discovery & Target Validation
- Enables functional interrogation of oncogenic drivers and tumor suppressor loss in ATC.
- Supports mechanistic de-risking by modeling tumor progression and immune infiltration in vivo.
- Facilitates target validation through reproducible tumor dynamics and survival endpoints.
- Provides a platform for evaluating the biological impact of candidate interventions.
Screening & Assay Development
- Delivers standardized, immunocompetent tumor samples for downstream assay development.
- Enables quantitative measurement of tumor size, metastasis, and immunohistochemical markers.
- Supports reproducibility and scalability for compound screening in a disease-relevant context.
- Prepares validated biological systems for reliable evaluation of small molecules and immunotherapies.
Translational & Preclinical Research
- Aligns preclinical models with human ATC pathophysiology and immune microenvironment.
- Enables translational biomarker discovery through matched tumor and metastatic tissue analysis.
- Supports risk-adjusted advancement decisions by modeling survival and metastatic burden.
- Provides continuity from discovery through preclinical validation for ATC-focused portfolios.
Pipeline & Workflow Integration
The mATC model integrates into the discovery-to-preclinical continuum, supporting target validation, lead identification, and translational research for ATC.
- Discovery Biology: Facilitates hypothesis testing on gene function and tumor progression in a unified genetic background.
- Screening: Provides reproducible, quantitative outputs for tumor growth, metastasis, and immune cell infiltration.
- Analytics: Enables statistical comparison of tumor dynamics, survival, and pathological features across experimental arms.
- Translational Research: Bridges preclinical findings to human ATC by modeling relevant immune and metastatic phenotypes.
- Enterprise Reuse: Offers a reusable, standardized platform for iterative drug and biomarker evaluation in ATC research.
Operational & Enterprise Impact
- Scientific Value: Increases predictive confidence and reduces mechanistic ambiguity in ATC target validation.
- Operational Value: Standardizes sample collection, tumor measurement, and immunopathological analysis.
- Strategic Value: Improves go/no-go decisions and capital efficiency by modeling clinically relevant endpoints.
- Portfolio Impact: Enables risk-adjusted prioritization and advancement of ATC therapeutic candidates.
Implementation Considerations
- Requires expertise in genetic engineering, murine handling, and immunohistochemistry.
- Needs access to animal facilities, imaging, and quantitative pathology infrastructure.
- Demands cross-team standardization for sample processing and data analysis.
- Adaptation to other thyroid cancer subtypes may require additional genetic modifications.
- Model throughput and scalability are limited by animal cohort size and induction timelines.
