MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer

Abstract

Communication between cancer cells and the tumor microenvironment results in the modulation of complex signaling networks that facilitate tumor progression. Here, we describe a new mechanism of intercellular communication originating from large oncosomes (LO), which are cancer cell-derived, atypically large (1-10 mm) extracellular vesicles (EV). We demonstrate that, in the context of prostate cancer, LO harbor sustained AKT1 kinase activity, nominating them as active signaling platforms. Active AKT1 was detected in circulating EV from the plasma of metastatic prostate cancer patients and was LO specific. LO internalization induced reprogramming of human normal prostate fibroblasts as reflected by high levels of a-SMA, IL6, and MMP9. In turn, LO-reprogrammed normal prostate fibroblasts stimulated endothelial tube formation in vitro and promoted tumor growth in mice. Activation of stromal MYC was critical for this reprogramming and for the sustained cellular responses elicited by LO, both in vitro and in vivo in an AKT1-dependent manner. Inhibition of LO internalization prevented activation of MYC and impaired the tumor-supporting properties of fibroblasts. Overall, our data show that prostate cancer-derived LO powerfully promote establishment of a tumor-supportive environment by inducing a novel reprogramming of the stroma. This mechanism offers potential alternative options for patient treatment. Cancer Res; 77(9); 2306-17.Ó2017 AACR.

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma

“…Importantly, LO are 1000 times the size of Exo by volume, harbour distinct molecular cargo when compared to Exo and are tumour-specific [23]. In this study, we purified and characterized the DNA in L-EVs (surrogate of LO) and S-EVs (surrogate of Exo) from the same cancer cell source as well as from PCa mouse and patient plasma.…”

Proteomic Analysis of Extracellular Vesicles for Cancer Diagnostics

“…It is important to note that “oncosomes/large oncosomes” was originally coined to describe the unusually large EVs, even though the term is sometimes referred to as oncogenic EVs released by cancer cells . Oncosomes have been reported to transfer functional miRNAs and proteins to cancer‐associated fibroblasts (CAFs) to promote prostate cancer metastasis …”

Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside

“…ABs from transformed rat embryonic fibroblasts delivered oncogenes to mouse embryonic fibroblasts, resulting in aneuploidy and oncogenic change. Besides exosomes, MVs and ABs, large oncosomes also carry oncogenic messages mediating the communication between cancer cells and fibroblasts (159). In PCa, large oncosomes derived from cancer cells were shown to contain active AKT1.…”