LAUSR

Renal cell carcinoma (RCC) is estimated to result in 79,000 new cases and 13,920 deaths in 2022. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and is characterized by a highly vascularized tumor microenvironment (TME). While current anti-angiogenic therapies targeting VEGF signaling are initially effective, almost all patients develop resistance to these therapies. Therefore, there is a need to identify clinically relevant alternative molecular targets to suppress tumor angiogenesis and progression in ccRCC. We previously discovered transcriptional upregulation of actin-binding profilin1 (Pfn1) in tumor-associated vascular endothelial cells (EC) in ccRCC and higher expression of Pfn1 correlated with adverse clinical prognosis. The goal of the present work was to further explore whether genetic manipulation of Pfn1 specifically in EC has therapeutic benefit in kidney cancer. We found that triggering vascular endothelial Pfn1 gene deletion, either in a widespread manner or locally in a kidney-restricted manner, suppresses tumor initiation and/or growth progression of pre-established kidney tumors in syngeneic mouse models. Loss of endothelial Pfn1 dramatically impacts the TME characterized by prominent suppression of tumor angiogenesis with massive tumor cell death and reduction of tumor-infiltrating immune cells. By performing cytokine array and Luminex assays of tumor lysates, we further identified Pfn1-dependent downregulation of several pro-angiogenic cell-secreted factors and pro-inflammatory cytokines that are major drivers of tumor progression in RCC including VEGF, endothelin-1, Cyr61, Macrophage Inflammatory Protein, G-CSF and IL6 in vivo. As a clinical correlate for mouse model data, we performed multiplexed quantitative immunohistochemistry analyses of human ccRCC specimens constructed on tissue microarray which also showed a positive correlation between Pfn1 expression (either in endothelial cells or tumor cells) and tumor infiltration of predominantly macrophages. Furthermore, through small molecule screening, we identified a novel inhibitor of the Pfn1-actin interaction (Pfn1i) and showed its ability to inhibit tumor angiogenesis and growth aggressiveness of tumor cells resembling various genetic landscapes of human ccRCC. Collectively, these findings establish endothelial Pfn1 as a critical regulator of TME and tumor progression in RCC, and provide a proof-of-concept for targeting Pfn1 as a potentially novel therapeutic strategy in RCC. Citation Format: David M. Gau, Abigail Allen, Andrew Daoud, Jessica Kunkel, Stefan Duensing, Partha Roy. Genetic disruption of vascular endothelial profilin-1 impacts tumor microenvironment supressing tumorigenicity of renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4584.