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Updated: Sep 13, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Treatment-Induced Gene Expression Changes in Metastatic Renal Cell Carcinoma: Insights from a Syngeneic Mouse Model
Ko Okabe1, Toshiaki Tanaka1, Tetsuya Shindo1
1Department of Urology, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
Abstract:
This study aimed to clarify the alterations in gene expression in metastatic renal cell carcinoma (mRCC) during disease progression and in response to treatment with immune checkpoint inhibitors using a syngeneic mouse mRCC model. RENCA cells were orthotopically implanted in BALB/c mice. Mice received first-line treatment with cabozantinib, anti-PD-1 antibody, or a combination. Tumor progression was monitored using serial micro-computed tomography. Lung metastasis samples were collected, and RNA sequencing was performed. Mice with apparent disease progression received second-line treatment with axitinib, everolimus, or lenvatinib after combination therapy. The median overall survival was 28, 34, 34, and 49 days in untreated mice and those treated with cabozantinib, anti-PD-1, or their combination, respectively (p < 0.05). RNA sequencing revealed upregulation of the fibroblast growth factor pathway in lung metastases after monotherapy, whereas mTOR pathway activation was observed only after combination therapy. Treatment-specific gene expression changes occur in mRCC, suggesting that the optimal target for sequential therapy in mRCC varies depending on prior treatment.
Insights
This study investigated gene expression changes in metastatic renal cell carcinoma (mRCC) during progression and response to immune checkpoint inhibitors. Findings suggest that optimal sequential therapy targets in mRCC depend on prior treatments.
Area of Science:
- Oncology
- Translational Research
- Immunotherapy
Background:
- Metastatic renal cell carcinoma (mRCC) remains a significant clinical challenge.
- Understanding treatment-induced gene expression changes is crucial for optimizing therapy.
Purpose of the Study:
- To investigate gene expression alterations in mRCC during disease progression.
- To analyze gene expression changes in response to first-line treatments (cabozantinib, anti-PD-1, combination) and second-line therapies.
- To identify potential therapeutic targets for sequential treatment strategies.
Main Methods:
- Utilized a syngeneic mouse mRCC model (RENCA cells in BALB/c mice).
- Administered first-line treatments: cabozantinib, anti-PD-1 antibody, or combination therapy.
- Monitored tumor progression via micro-computed tomography.
- Performed RNA sequencing on lung metastasis samples.
- Assessed second-line treatments (axitinib, everolimus, lenvatinib) after combination therapy.
Main Results:
- Combination therapy significantly improved median overall survival compared to monotherapy or no treatment (49 days vs. 28-34 days).
- RNA sequencing revealed fibroblast growth factor pathway upregulation after monotherapy.
- mTOR pathway activation was observed specifically after combination therapy.
- Gene expression changes were treatment-specific.
Conclusions:
- Immune checkpoint inhibitors and targeted therapies induce distinct gene expression profiles in mRCC.
- Sequential therapy effectiveness in mRCC is influenced by prior treatment regimens.
- Identifying treatment-specific pathway activation can guide the selection of subsequent therapies.
