Cracking the riddle of dedifferentiated liposarcoma: is EV-MDM2 a key?

Abstract

Dedifferentiated liposarcoma (DDLPS) is molecularly characterized by wt p53 and MDM2 gene amplification causing MDM2 protein overproduction , the key oncogenic process in DDLPS. Commonly located in fat-bearing retroperitoneal areas, almost 60% of DDLPS patients undergo multifocal recurrence, typically amenable to palliative treatment only, and occasionally develop distant metastasis. These factors lead to an abysmal 10% 10 year overall survival rate. Tumor cell-derived extracellular vesicles (EVs) can facilitate loco-regional malignancy dissemination by depositing molecular factors that participate in the development of pre-metastatic niches for tumor cell implantation and growth. High number of MDM2 DNA molecules was identified within EVs from DDLPS patient serum (ROC vs normal; 0.95) as well as from DDLPS cell lines. This MDM2 DNA could be transferred to preadipocytes (P-a), a major and ubiquitous cellular component of the DDLPS tumor microenvironment (TME), with subsequent P-a production of matrix metalloproteinase 2 (MMP2), a critical component in the metastatic cascade. From here the hypothesis that the DDLPS microenvironment (specifically P-a cells) may participate in DDLPS recurrence events. Since multifocal loco-regional DDLPS spreading is the main cause of the remarkably high lethality of this disease, a better understanding of the underlying oncogenic processes and their regulatory mechanisms is essential to improve the outcome of this devastating disease.

Comparison of three-dimensional cell culture techniques of dedifferentiated liposarcoma and their integration with future research

“…Previous research has shown that microfluidic devices can better preserve extracellular vesicle (EV) cargo during the isolation of particles ( Perut et al, 2019 ; Casadei et al, 2021 ), providing us with a unique opportunity to gain insights into the mechanisms underlying DDLPS recurrence events. Previously, we have observed high levels of MDM2 DNA in EVs derived from DDLPS patient serum and cell lines, which was transferable to preadipocytes at the microenvironment level ( Casadei et al, 2019 ; Casadei and Pollock, 2020 ). Building on this observation, we hypothesize that the DDLPS microenvironment plays a crucial role in DDLPS recurrence.…”

Cross‐flow microfiltration for isolation, selective capture and release of liposarcoma extracellular vesicles

“…The diagnostic and prognostic challenges prompted us and other researchers to study mechanisms of progression of this disease and to explore the use of circulating biomolecules like micro‐ribonucleic acids (miRNAs) and deoxyribonucleic acid (DNA) that could serve as potential biomarkers for early stage detection and are accessible through bodily fluids (He et al., 2015; Jin et al., 2012). Past work has shown that miR‐25, miR‐92, and MDM2 DNA may be associated with the development and progression of DDLPS (Casadei & Pollock, 2020; Casadei et al., 2017, 2019). Moreover, it was discovered that these miRNAs and DNA serve as cargo contained within extracellular vesicles (EVs), released from tumors and present in the circulatory system (Casadei & Pollock, 2020; Casadei et al., 2017, 2019).…”

“…Past work has shown that miR‐25, miR‐92, and MDM2 DNA may be associated with the development and progression of DDLPS (Casadei & Pollock, 2020; Casadei et al., 2017, 2019). Moreover, it was discovered that these miRNAs and DNA serve as cargo contained within extracellular vesicles (EVs), released from tumors and present in the circulatory system (Casadei & Pollock, 2020; Casadei et al., 2017, 2019).…”