Open Access
ARTICLE
uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells
Elena Andreucci*1, 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*†1
* Department of Experimental and Clinical Biomedical Sciences “Mario Serio,” University of Florence, Florence, Italy
† Center of Excellence for Research, Transfer and High Education DenoTHE University of Florence, Florence, Italy
‡ Laboratory of Nanotecnology, IRCCS Istituto Tumori “Giovanni Paolo II,” Bari, Italy
§ Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II,” Bari, Italy
¶ Rare Tumors and Melnaoma Unit, IRCCS Istituto Tumori “Giovanni Paolo II,” Bari, Italy
Oncology Research 2020, 28(9), 873-884. https://doi.org/10.3727/096504021X16273798026651
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.
Keywords
Cite This Article
Andreucci, E., Laurenzana, A., Peppicelli, S., Biagioni, A., Margheri, F. et al. (2020). uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells.
Oncology Research, 28(9), 873–884. https://doi.org/10.3727/096504021X16273798026651