Disruption of tubular Flcn expression as a mouse model for renal tumor induction
Jindong Chen1,2, Dachuan Huang3, Isabelle Rubera4
1Kidney Cancer Research Laboratory, Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
Abstract:
The study of kidney cancer pathogenesis and its treatment has been limited by the scarcity of genetically defined animal models. The FLCN gene that codes for the protein folliculin, mutated in Birt-Hogg-Dubé syndrome, presents a new target for mouse modeling of kidney cancer. Here we developed a kidney-specific knockout model by disrupting the mouse Flcn in the proximal tubules, thus avoiding homozygous embryonic lethality or neonatal mortality, and eliminating the requirement of loss of heterozygosity for tumorigenesis. This knockout develops renal cysts and early onset (6 months) of multiple histological subtypes of renal neoplasms featuring high tumor penetrance. Although the majority of the tumors were chromophobe renal cell carcinomas in affected mice under 1 year of age, papillary renal cell carcinomas predominated in the kidneys of older knockout mice. This renal neoplasia from cystic hyperplasia at 4 months to high-grade renal tumors by 16 months represented the progression of tumorigenesis. The mTOR and TGF-β signalings were upregulated in Flcn-deficient tumors, and these two activated pathways may synergetically cause renal tumorigenesis. Treatment of knockout mice with the mTOR inhibitor rapamycin for 10 months led to the suppression of tumor growth. Thus, our model recapitulates human Birt-Hogg-Dubé kidney tumorigenesis, provides a valuable tool for further study of Flcn-deficient renal tumorigenesis, and tests new drugs/approaches to their treatment.
Insights
Researchers created a new mouse model for kidney cancer by targeting the FLCN gene. This model shows promise for studying Birt-Hogg-Dubé syndrome and testing new cancer treatments.
Area of Science:
- Oncology
- Genetics
- Nephrology
Background:
- Kidney cancer research is hindered by a lack of genetically defined animal models.
- The FLCN gene, when mutated in Birt-Hogg-Dubé syndrome, offers a potential target for kidney cancer modeling.
Purpose of the Study:
- To develop a kidney-specific mouse model for studying FLCN-deficient renal tumorigenesis.
- To investigate the role of mTOR and TGF-β signaling in kidney cancer development.
- To evaluate the efficacy of rapamycin in treating FLCN-deficient kidney tumors.
Main Methods:
- Generated a kidney-specific knockout mouse model by disrupting the mouse Flcn gene in proximal tubules.
- Monitored tumor development, histological subtypes, and progression over time.
- Analyzed mTOR and TGF-β signaling pathways in Flcn-deficient tumors.
- Treated knockout mice with the mTOR inhibitor rapamycin.
Main Results:
- The Flcn knockout model developed renal cysts and multiple histological subtypes of renal neoplasms with high penetrance.
- Tumor progression was observed from cystic hyperplasia to high-grade renal tumors.
- mTOR and TGF-β signaling pathways were upregulated in Flcn-deficient tumors.
- Rapamycin treatment suppressed tumor growth in knockout mice.
Conclusions:
- The developed mouse model effectively recapitulates human Birt-Hogg-Dubé kidney tumorigenesis.
- This model serves as a valuable tool for studying Flcn-deficient renal tumorigenesis and therapeutic strategies.
- Targeting mTOR signaling shows potential for treating FLCN-associated kidney cancer.
