Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype
Shaolin Ma, Michael H. McGuire, Lingegowda S. Mangala, Sanghoon Lee, Elaine Stur, Wen Hu, Emine Bayraktar, Alejandro Villar‐Prados, Cristina Ivan, Sherry Y. Wu, Akira Yokoi, Santosh K. Dasari, Nicholas B. Jennings, Jinsong Liu, Gabriel Lopez‐Berestein, Prahlad T. Ram, Anil K. Sood
Abstract
Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.