A key question in cancer biology is how mutations that disrupt common cellular pathways can lead to tumours in only certain tissues. In a new study published in Nature Communications, researchers led by Samvid Kurlekar and Peter Ratcliffe of the Ratcliffe group have explored this question through the lens of von Hippel–Lindau (VHL) disease. VHL is a hereditary cancer syndrome characterised by the growth of cysts and tumours (both benign and malignant) in various organs, including the eyes, cerebellum, kidneys, spinal cord, pancreas, and adrenal glands.
In VHL disease, mutations in the VHL ubiquitin ligase lead to the abnormal stabilisation of hypoxia-inducible factors (HIFs), transcriptional regulators that normally respond to low oxygen. When VHL is mutated, the HIF-1α and HIF-2α proteins escape degradation and remain continuously active, upregulating their target genes regardless of oxygen levels. This dysregulation represents one of the earliest - or truncal - events in the development of clear-cell renal carcinoma (ccRCC), the predominant malignancy of the kidney.
To understand why the effects of VHL inactivation are restricted to specific renal cell types, the team used an oncogenic tagging strategy so that VHL-deficient cells would express a fluorescent marker, allowing them to be traced and analysed from the moment of gene loss. By selectively deleting either HIF1A or EPAS1 (the genes encoding HIF-1α and HIF-2α, respectively), they were able to study how each isoform shaped early oncogenic behaviour in the kidney.
Their findings suggest that the tissue-specificity of VHL-associated oncogenesis arises from the isoform-specific and cell type-specific actions of the two HIFa isoforms. For example, in the renal papilla, VHL mutation triggered the loss of affected cells in a HIF-1α dependent manner, possibly explaining why VHL-associated cancers don’t arise from this region and marking HIF-1α as potentially anti-tumorigenic. In contrast, within the proximal tubule - the compartment from which ccRCC is thought to originate - VHL loss caused cells to survive and proliferate, but only when both HIF-1α and HIF-2α were intact. This cooperation between isoforms appears essential for the early expansion of potential cancer-initiating cells.
The team also conducted single-cell RNA sequencing of more than 140,000 tagged cells to explore the molecular basis for these outcomes. They found that HIF-1α primarily activated genes involved in glycolysis and cellular metabolism, supporting energy production, while HIF-2α upregulated genes controlling metabolism, extracellular-matrix organisation, and dedifferentiation - features associated with cancer progression. These temporal and spatial distinctions help to explain how a single genetic event can produce different outcomes across cell types.
Importantly, the research also found that the HIF-2α-dependent gene signatures identified in early VHL-deficient cells persist in established ccRCC, strengthening the rationale for therapeutic inhibition of HIF-2α. Drugs such as belzutifan, already approved for advanced disease, may therefore hold potential in preventing tumour initiation in individuals with VHL mutations.
Together, the study provides a mechanistic explanation for the tissue specificity of VHL-associated oncogenesis and illustrates how distinct HIF isoform activities determine whether cells adapt, die, or undergo malignant transformation following loss of VHL.