@Article{096504021X16273798026651,
AUTHOR = {Elena Andreucci, Anna Laurenzana, Silvia Peppicelli, Alessio Biagioni, Francesca Margheri, Jessica Ruzzolini, Francesca Bianchini, Gabriella Fibbi, Mario Del Rosso, Chiara Nediani, Simona Serratì, Livia Fucci, Michele Guida, Lido Calorini},
TITLE = {uPAR Controls Vasculogenic Mimicry Ability Expressed by  Drug-Resistant Melanoma Cells},
JOURNAL = {Oncology Research},
VOLUME = {28},
YEAR = {2020},
NUMBER = {9},
PAGES = {873--884},
URL = {http://www.techscience.com/or/v28n9/48482},
ISSN = {1555-3906},
ABSTRACT = {Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor 
survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of 
melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, 
a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to 
organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenibresistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research 
aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma 
cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent 
experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of 
melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant 
phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting 
and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are 
characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and 
using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of 
VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged 
as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid 
progression and dissemination of the disease.},
DOI = {10.3727/096504021X16273798026651}
}