Actin-binding protein Profilin1 promotes aggressiveness of clear cell renal cell carcinoma cells.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, has a poor clinical outcome. A hallmark of ccRCC is genetic loss-of-function of Von-Hippel Lindau (VHL) that leads to a highly vascularized tumor microenvironment. While many ccRCC patients initially respond to anti-angiogenic therapies, virtually all develop progressive, drug-refractory disease. Given the role of dysregulated expressions of cytoskeletal and cytoskeleton-regulatory proteins in tumor progression, we performed analyses of The Cancer Genome Atlas (TCGA) transcriptome data for different classes of actin-binding proteins to demonstrate that increased mRNA expression of profilin1 (Pfn1), Arp3, cofilin1, Ena/VASP and CapZ, are indicators of poor prognosis in ccRCC. Focusing further on Pfn1, we performed immunohistochemistry-based classification of Pfn1 staining in tissue microarrays, which indicated Pfn1-positivity in both tumor and stromal cells; however, the vast majority of ccRCC tumors tend to be Pfn1-positive selectively in stromal cells only. This finding is further supported by evidence for dramatic transcriptional upregulation of Pfn1 in tumor-associated vascular endothelial cells (VEC) in the clinical specimens of ccRCC. In vitro studies support the importance of Pfn1 in proliferation and migration of RCC cells, and in soluble Pfn1's involvement in VEC-tumor cell crosstalk. Furthermore, proof-of-concept studies demonstrate that treatment with a novel computationally designed Pfn1-actin interaction inhibitor identified herein reduces proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo. Based on these findings, we propose a potentiating role for Pfn1 in promoting tumor cell aggressiveness in the setting of ccRCC.

The Journal of biological chemistry. 2020 Sep 03 [Epub ahead of print]

Abigail Allen, David Gau, Paul Francoeur, Jordan Sturm, Yue Wang, Ryan Martin, Jodi Maranchie, Anette Duensing, Adam Kaczorowski, Stefan Duensing, Lily Wu, Michael T Lotze, David Koes, Walter J Storkus, Partha Roy

University of Pittsburgh, United States., Bioengineering, University of Pittsburgh, United States., Department of Bioengineering, University of Pittsburgh, United States., Urology, University of Pittsburgh, United States., Heidelberg School of Medicine, Germany., Heidelberg University Hospital., University of California Los Angeles, United States., University of Pittsburgh.