Spatial and functional profiling tumor evolution trajectories and microenvironment interactions of VHL driven renal cancers

Renal cell carcinomas (RCC), particularly clear cell renal cell carcinoma (ccRCC), are among the most chemotherapy-resistant cancers, driven predominantly by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene in over 90% of cases and leads to the stabilization of hypoxia-inducible factor 2α (HIF2A), triggering widespread changes in gene expression, metabolic reprogramming, and angiogenesis. While advancements in systemic therapies targeting the VEGF pathway and immune checkpoints have shown promise, understanding intra-tumoral heterogeneity and its impact on therapy resistance remains a significant challenge. Cellular function is intricately dependent on its local environment, yet bulk and single-cell profiling lacking the spatial resolution necessary to decipher the complex biomolecular and cellular interactions within the native tumor microenvironment. This proposal seeks to address critical knowledge gaps by leveraging spatially resolved transcriptomics, genomic engineering, and multi-omics methodologies to create a comprehensive spatial atlas of treatment-resistant ccRCC. Specifically, the study hypothesizes that therapy-driven sub-clonal selection promotes aggressive phenotypes, characterized by the extinction of HIF signaling, with spatially distinct subclones exhibiting unique cellular states and molecular dependencies. By integrating cutting-edge self-barcoding technology and spatial multi-omics, the project will identify sub-clonal transcriptomic fingerprints and spatial heterogeneity across the ccRCC tumor landscape. The proposed research will generate cross-species spatially resolved multi-omics data to map tumor evolution trajectories, identify molecular drivers of treatment resistance, and unravel interactions between cancer cells, immune components, and stromal elements. These insights will pave the way for the discovery of novel biomarkers to stratify patients likely to benefit from HIF inhibitors and uncover new molecular dependencies essential for the survival of HIFi-resistant cancer cells. By bridging spatial and molecular insights, this work has the potential to transform therapeutic strategies and improve outcomes for ccRCC patients. Project Number: 1K99CA307136-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Li Zhang | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $131,933 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CDPT-N (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11280965