Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Loss of the von Hippel-Lindau (VHL) tumor suppressor gene is a key event in clear cell renal cell carcinoma (ccRCC).
• Intratumoral heterogeneity regarding VHL gene status is increasingly recognized but its functional impact remains under-explored.
• Understanding VHL heterogeneity is crucial for developing effective ccRCC treatments.

Purpose of the Study:

• To investigate the impact of intratumoral VHL heterogeneity on ccRCC progression and metastasis.
• To elucidate the cooperative mechanisms driving metastasis in heterogeneous ccRCC tumors.
• To identify potential therapeutic targets for inhibiting ccRCC metastasis.

Main Methods:

• Engineered VHL gene deletion in four RCC models, including a novel primary cell line.
• Comparative analysis of VHL-expressing (VHL+) and VHL-deleted (VHL-KO) cells regarding proliferation, motility, and epithelial-to-mesenchymal transition (EMT).
• Assessment of metastatic potential in tumors with mixed VHL+ and VHL-KO populations and evaluation of Periostin (POSTN) as a mediator.

Main Results:

• VHL-KO cells showed increased motility and EMT but reduced proliferation and tumorigenicity compared to VHL+ cells.
• Combined VHL+ and VHL-KO tumors exhibited significant lung metastasis, unlike tumors with homogeneous VHL status.
• VHL-KO cells stimulated proliferation and motility of adjacent VHL+ cells, mediated by POSTN secretion.
• POSTN blockade or genetic deletion significantly reduced lung metastasis in preclinical models.

Conclusions:

• Intratumoral VHL heterogeneity creates a cooperative microenvironment that promotes ccRCC metastasis.
• VHL-deficient cells can drive metastatic potential in VHL-proficient ccRCC cells through paracrine signaling.
• Periostin (POSTN) is a critical mediator of ccRCC metastasis, making it a promising therapeutic target.