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

Abstract

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL−) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis

“…To evaluate the effects of Vhl loss on tumor growth dynamics and specific tumor microenvironmental features, Renca Vhl WT or Vhl -KO cells were grown subcutaneously in BALB/c mice. As previously observed, Vhl -KO tumors across clones grew significantly more slowly than did Vhl WT tumors ( Figure 3, A and B ) ( 20 , 21 ). Considering that this effect may derive from both cell-intrinsic and cell-extrinsic factors, we next hypothesized that the slower-growing Vhl -KO tumors with increased angiogenesis might also display altered immune infiltration.…”

Discovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader

“…VHL is one of the most widely utilized E3 ligases for the development of PROTACs. However, VHL can be defective in some cancer types such as renal cell carcinoma (RCC). , PROTACs that recruit different E3 ligases could be particularly useful for inhibiting the growth of VHL-defective cancer cells. Therefore, we evaluated whether compound 1 can be utilized in VHL-defective cancer cells where VHL-recruiting bridged PROTACs such as MS147 would fail.…”

Disproportionality Analysis of Lenvatinib‐Caused Gastrointestinal Perforation in Cancer Patients: A Pharmacovigilance Analysis Based on the US Food and Drug Administration Adverse Event Reporting System

“…Treatment for kidney cancer typically excludes the management of the esophageal site, except in cases where kidney cancer has metastasized, affecting specific areas such as the lungs, which may directly impact the esophagus through lung cancer. 27 As a result of the unique location of the tumor, thyroid cancer can directly impact the natural condition and functioning of the esophagus. This can subsequently heighten the risk of complications, including tumor infiltration, tumor necrosis, and a tight fit between the nodule and the esophagus.…”