(P 395) TARGETING CD44-MEDIATED IRON ENDOCYTOSIS IN DESMOID FIBROMATOSIS

Objective: CD44 is a transmembrane glycoprotein that is linked to various biological processes reliant on the epigenetic plasticity of cells. During epithelial-mesenchymal transition, CD44 mediates endocytosis of extracellular iron interacting with hyaluronates (HA) and promotes the development of metastases. In desmoid fibromatosis (DF), HA have been shown to colocalize with CD44, and high CD44 is associated with relapse after surgery. Moreover, CD44 is upregulated by the Wnt/-catenin pathway which is consistently activated in DF. Therefore, we decided to study whether in DF, a CD44-dependent iron endocytosis is occurring and could promote DF cell survival and proliferation.

Methods: Fresh samples of progressive tumors from DF patients collected during surgery were analyzed by flow cytometry, and RNA sequencing (RNAseq) was performed on sorted CD44-high and CD44-low DF cells. Fresh primary DF cells were dissociated and cell viability was measured in vitro after exposure to various iron chelators. A cohort of 40 clinically-annotated pretreatment DF was further studied by RNAseq and multiplex immunohistochemistry.

Results: We observed that all DF cells present high levels of lysosomal iron. The levels of iron and CD44 at the plasma membrane are correlated and are increased in DF tissues compared to healthy adjacent tissues. CD44 and ferritin levels were similarly elevated in both progressive and non-progressive DF by bulk RNAseq or immunohistochemistry in the clinically annotated tumor cohort (n=40). RNAseq on sorted CD44-high DF cells identified an increase of cell cycle-related genes compared to CD44-low DF cells. Finally, the iron chelators ironomycin and deferiprone decreased cell viability of primary DF cells in vitro.

Conclusion: Altogether these data demonstrate that targeting CD44 and iron metabolism could be a valuable strategy in the treatment of desmoid fibromatosis.