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

Award Number: K99CA307136
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Spatial and functional profiling tumor evolution trajectories and microenvironment interactions of VHL driven renal cancers - Project Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $131,933 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Research Manpower	000	1	4/10/2026	NEW	$131,933
														Subtotal = $131,933

Grand Total All Awards = $131,933

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

Award Number: K99CA307136

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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