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Updated: Sep 30, 2025
Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
Published on: April 29, 2014
Microphysiological model of renal cell carcinoma to inform anti-angiogenic therapy
María Virumbrales-Muñoz1, Jose M Ayuso2, Jack R Loken3
1Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 1111 Highland Avenue, Madison, WI, 53705, USA; University of Wisconsin Carbone Cancer Center, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI, 53705, USA.
Abstract:
Renal cell carcinomas are common genitourinary tumors characterized by high vascularization and strong reliance on glycolysis. Despite the many available therapies for renal cell carcinomas, first-line targeted therapies, such as cabozantinib, and durable reaponses are seen in only a small percentage of patients. Yet, little is known about the mechanisms that drive response (or lack thereof). This dearth of knowledge can be explained by the dynamic and complex microenvironment of renal carcinoma, which remains challenging to recapitulate in vitro. Here, we present a microphysiological model of renal cell carcinoma, including a tubular blood vessel model of induced pluripotent stem cell-derived endothelial cells and an adjacent 3D carcinoma model. Our model recapitulated hypoxia, glycolic metabolism, and sprouting angiogenesis. Using our model, we showed that cabozantinib altered cancer cell metabolism and decreased sprouting angiogenesis but did not restore barrier function. This microphysiological model could be helpful to elucidate, through multiple endpoints, the contributions of the relevant environmental components in eliciting a functional response or resistance to therapy in renal cell carcinoma.
Insights
This study introduces a new microphysiological model for renal cell carcinoma (RCC) to understand treatment resistance. The model revealed how cabozantinib affects RCC metabolism and angiogenesis but not barrier function.
Area of Science:
- Oncology
- Biomedical Engineering
- Cancer Biology
Background:
- Renal cell carcinoma (RCC) is a common genitourinary tumor with high vascularization and reliance on glycolysis.
- Current first-line targeted therapies like cabozantinib show limited durable responses in a small patient percentage.
- Mechanisms driving treatment response or resistance in RCC are poorly understood due to the complex tumor microenvironment.
Purpose of the Study:
- To develop and utilize a novel microphysiological model to study renal cell carcinoma.
- To investigate the effects of cabozantinib on RCC in a more physiologically relevant in vitro system.
- To elucidate the contributions of microenvironmental components to therapeutic response and resistance in RCC.
Main Methods:
- Development of a microphysiological model comprising induced pluripotent stem cell-derived endothelial cells forming a tubular blood vessel and an adjacent 3D carcinoma model.
- Recapitulation of key renal cell carcinoma microenvironment features including hypoxia, glycolic metabolism, and sprouting angiogenesis.
- Assessment of cabozantinib's effects on cancer cell metabolism, angiogenesis, and endothelial barrier function within the model.
Main Results:
- The developed microphysiological model successfully recapitulated hypoxia, glycolic metabolism, and sprouting angiogenesis characteristic of renal cell carcinoma.
- Cabozantinib treatment altered cancer cell metabolism and reduced sprouting angiogenesis.
- Despite its effects on metabolism and angiogenesis, cabozantinib did not restore endothelial barrier function in the model.
Conclusions:
- A novel microphysiological model provides a valuable platform for studying renal cell carcinoma and its microenvironment.
- The model demonstrates that cabozantinib impacts RCC metabolism and angiogenesis but does not fully restore vascular barrier integrity.
- This system offers a promising approach to investigate therapeutic response and resistance mechanisms in renal cell carcinoma by dissecting microenvironmental contributions.
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