Abstract Biallelic mutation of the VHL tumour suppressor is an early, truncal event in the pathogenesis clear cell kidney cancer and entrains constitutive activation of hypoxia pathways orchestrated by the HIF transcription factors, HIF-1 and HIF-2. However, despite ubiquitous expression of this massive physiological pathway, VHL mutation leads to highly tissue-specific patterns of tumour formation. While the mechanisms underlying this response are poorly understood, we hypothesised that they may reflect context-dependent consequences of HIF activation operating early in the development of the cancer. To study this, we used an oncogenic tagging strategy in which Vhl-mutant cells were marked by TdTomato enabling their observation, retrieval and analysis over time and coupled Vhl deletion with inactivation of HIF-1 and/or HIF-2. This defined both cell-type and HIF isoform-specific responses to VHL inactivation. Specifically, we identified heterogenous effects, with time-limited proliferation and elimination of specific cell types defining a proximal tubular cell class with oncogenic potential. Notably, we revealed early involvement of HIF-2 in promoting proliferation within the proximal tubular epithelium as well as longer-term adaptive changes. This work suggests that early events shape the cell-type specificity of oncogenesis, providing a focus for mechanistic understanding and therapeutic targeting. Citation Format: David R. Mole. The role of hypoxia pathways in kidney cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr IA018.
David R. Mole (Fri,) studied this question.