Modeling clear cell renal cell carcinoma and therapeutic implications

Abstract

Renal cell carcinoma (RCC) comprises a diverse group of malignancies arising from the nephron. The most prevalent type, clear cell renal cell carcinoma (ccRCC), is characterized by genetic mutations in factors governing the hypoxia signaling pathway, resulting in metabolic dysregulation, heightened angiogenesis, intratumoral heterogeneity, and deleterious tumor microenvironmental (TME) crosstalk. Identification of specific genetic variances has led to therapeutic innovation and improved survival for patients with ccRCC. Current barriers to effective long-term therapeutic success highlight the need for continued drug development using improved modeling systems. ccRCC preclinical models can be grouped into three broad categories: cell line, mouse, and 3D models. Yet, the breadth of important unanswered questions in ccRCC research far exceeds the accessibility of model systems capable of carrying them out. Accordingly, we review the strengths, weaknesses, and therapeutic implications of each model system that are relied upon today.

Figure 1.

Advantages and disadvantages of model system platforms in RCC. Advantages and ideal applications, and disadvantages of traditional cell line, organoid, xenograft, and GEM models in RCC. As physiological relevance increases, ease of manipulation decreases.

Figure 2.

Location of ccRCC Associated Genes Human and Mouse Genome VHL and additional driver genes (SETD2, PBRM1, and BAP1) are located on chromosome 3p in the human genome. WGS identified two key events in the evolutionary progression of ccRCC: loss of one 3p arm during childhood or adolescents, followed an additional mutation in the remaining VHL allele. Corresponding genes in the mouse are located on chromosomes 6,9, and 14.

Figure 3.

Cre drivers in kidney epithelial cell deletion. Cre drivers in kidney epithelial cell gene specific deletion and tissues affected are outlined.

Figure 4.

Genetically engineered RCC mouse models. Strengths and limitations of relevant RCC GEM models, and the pathology recapitulated by each are outlined.