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Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment

1
The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
2
Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore
3
p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648, Singapore
4
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore
*
Author to whom correspondence should be addressed.
Academic Editor: Elaine Dunlop
Cancers 2021, 13(12), 2985; https://doi.org/10.3390/cancers13122985
Received: 2 May 2021 / Revised: 9 June 2021 / Accepted: 11 June 2021 / Published: 15 June 2021
(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)
In addition to the classical cell-to-cell communication patterns, extracellular vesicles (EVs) are instrumental in conveying molecular messages across cell types and have the potential to mediate changes at a tissue level. Since it is now appreciated that carcinomas are fundamentally reliant on two-way communication with activated cells in the tumor microenvironment, elucidating the roles of EVs exchange and of the cargo that is transferred is essential to obtain a thorough understanding of tumor progression. This study reveals that mutant p53 proteins—the result of the most frequent mutated gene in human cancer—are packed into EVs and delivered to neighboring cells with the potential to reprogram immune cells and subsequently establish a positive feedback loop that will enhance tumor progression. This non-cell autonomous role of mutant p53 is evidence of an extra layer of communication that is orchestrated by smaller vesicles that transfer oncogenic elements between cellular entities. Building on the foundation of our work on mutant p53, future studies may aim to characterize the potential activation of additional oncogenes, thus opening new paths of research at the interface of extracellular vesicles, cancer, and evolution.
Extracellular vesicles (EVs) shed by cancer cells play a major role in mediating the transfer of molecular information by reprogramming the tumor microenvironment (TME). TP53 (encoding the p53 protein) is the most mutated gene across many cancer types. Mutations in TP53 not only result in the loss of its tumor-suppressive properties but also results in the acquisition of novel gain-of-functions (GOF) that promote the growth of cancer cells. Here, we demonstrate that GOF mutant p53 proteins can be transferred via EVs to neighboring cancer cells and to macrophages, thus modulating them to release tumor supportive cytokines. Our data from pancreatic, lung, and colon carcinoma cell lines demonstrate that the mutant p53 protein can be selectively sorted into EVs. More specifically, mutant p53 proteins in EVs can be taken up by neighboring cells and mutant p53 expression is found in non-tumor cells in both human cancers and in non-human tissues in human xenografts. Our findings shed light on the intricate methods in which specific GOF p53 mutants can promote oncogenic mechanisms by reprogramming and then recruiting non-cancerous elements for tumor progression. View Full-Text
Keywords: mutant p53 protein; extracellular vesicles; tumor microenvironment mutant p53 protein; extracellular vesicles; tumor microenvironment
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MDPI and ACS Style

Bhatta, B.; Luz, I.; Krueger, C.; Teo, F.X.; Lane, D.P.; Sabapathy, K.; Cooks, T. Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment. Cancers 2021, 13, 2985. https://doi.org/10.3390/cancers13122985

AMA Style

Bhatta B, Luz I, Krueger C, Teo FX, Lane DP, Sabapathy K, Cooks T. Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment. Cancers. 2021; 13(12):2985. https://doi.org/10.3390/cancers13122985

Chicago/Turabian Style

Bhatta, Bibek, Ishai Luz, Christian Krueger, Fanny X. Teo, David P. Lane, Kanaga Sabapathy, and Tomer Cooks. 2021. "Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment" Cancers 13, no. 12: 2985. https://doi.org/10.3390/cancers13122985

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