Versican upregulation in Sézary cells alters growth, motility and resistance to chemotherapy

Abstract

Sézary syndrome (SéS) represents a leukemic variant of cutaneous T-cell lymphoma, whose etiology is still unknown. To identify dyregulated genes in SéS, we performed transcriptional profiling of Sézary cells (SCs) obtained from peripheral blood of patients with SéS. We identified versican as the highest upregulated gene in SCs. VCAN is an extracellular matrix proteoglycan, which is known to interfere with different cellular processes in cancer. Versican isoform V1 was the most commonly upregulated isoform in SCs. Using a lentiviral plasmid, we overexpressed versican V1 isoform in lymphoid cell lines, which altered their growth behavior by promoting formation of smaller cell clusters and by increasing their migratory capacity towards stromal cell-derived factor 1, thus promoting skin homing. Versican V1 overexpression exerted an inhibitory effect on cell proliferation, partially by promoting activation-induced cell death. Furthermore, V1 overexpression in lymphoid cell lines increased their sensitivity to doxorubicin and gemcitabine. In conclusion, we confirm versican as one of the dysregulated genes in SéS and describe its effects on the biology of SCs. Although versican overexpression confers lymphoid cells with increased migratory capacity, it also makes them more sensitive to activation-induced cell death and some chemotherapeutics, which could be exploited further for therapeutic purposes.

Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma

“…PI3K/mTOR as a therapeutic target in CTCL Another benefit of treating CTCL patients with PI3K/mTOR inhibitors could arise from the ability of PF-502 to abrogate tumor cell migration toward SDF-1. This chemokine is particularly abundant in the skin of SS patients owing to several mechanisms, such as the lack of the CD26 peptidase on the SS cell surface, inactivating SDF-1 (Narducci et al, 2006) and the overexpression of versican proteoglycan enhancing locomotion (Fujii et al, 2015). Moreover, we recently described the loss of the b-arrestin-2 gene in about 60% of SS cases, causing a defect in the CXCR4 internalization (Cristofoletti et al, 2019a).…”

Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance

“…Since SS cells do not express SDF-1 mRNA, but rather they seem to uptake the SDF-1 released from epithelial, dendritic and endothelial cells of the skin [23], we can speculate that SS cells move toward skin through a chemotactic gradient [23]. This hypothesis is further reinforced by the lack from SS cell surface of CD26 peptidase able to cleave and inactivate SDF-1 [23], by the versican overexpression, a proteoglycan that enhances the SS locomotion toward SDF-1 [45] and by the comparable levels of plasmatic SDF-1 found between HDs and SS individuals ( data not shown ).…”

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…In addition, versican was identified as one of the most upregulated genes in lymphocytes isolated from patients with Sezary syndrome which is a leukemic variant of cutaneous T cell lymphoma. In this setting, versican promoted the invasive and homing capacity of the lymphocytes from these patients (148). Interestingly, the cleavage of versican by ADAMTS enzymes is critical for T-cell trafficking in mouse models of influenza virus infection (149).…”