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

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Extracellular vesicles (EVs) mediate molecular transfer, reprogramming the tumor microenvironment (TME).
• TP53 mutations are common in cancer, leading to loss of tumor suppression and gain-of-function (GOF) promoting cancer growth.

Purpose of the Study:

• To investigate the transfer of GOF mutant p53 proteins via EVs.
• To determine how EVs carrying mutant p53 affect neighboring cells and the TME.

Main Methods:

• Analysis of extracellular vesicles (EVs) from pancreatic, lung, and colon carcinoma cell lines.
• Detection of mutant p53 protein sorting into EVs.
• Assessing EV uptake by neighboring cancer cells and macrophages.
• Evaluating the expression of mutant p53 in non-tumor cells in human cancers and xenografts.

Main Results:

• GOF mutant p53 proteins are selectively sorted into EVs shed by cancer cells.
• Mutant p53 proteins within EVs are transferred to neighboring cancer cells and macrophages.
• Uptake of mutant p53-carrying EVs leads to modulation of recipient cells, including cytokine release.
• Mutant p53 expression is observed in non-tumor cells within the tumor microenvironment.

Conclusions:

• GOF mutant p53 proteins can be intercellularly transferred via EVs.
• EV-mediated transfer of mutant p53 reprograms recipient cells, including macrophages, to support tumor progression.
• This mechanism highlights how mutant p53 hijacks cellular components to promote oncogenesis.