👤 Alessandro Poli

Hepcidin, a liver-derived hormone, is the central regulator of systemic iron homeostasis. Elevated hepcidin levels contribute to iron-refractory iron deficiency anemia (IRIDA) and anemia of inflammation, both characterized by restricted iron availability. Current treatments, such as parenteral iron infusions, are often ineffective and pose risks of adverse reactions, underscoring the need for alternative therapeutic strategies targeting hepcidin. We previously identified a novel hepcidin regulatory pathway involving liver heparan sulfate (HS) proteoglycans (HSPGs), which modulate receptor-ligand interactions through their sulfated HS chains. Recently, we found that halofuginone impairs HS biosynthesis and considered whether it could be used as a hepcidin modulator. Here, we demonstrate that in human hepatoma (Hep3B) cells, halofuginone inhibits both basal and BMP6-induced hepcidin expression and p-SMAD1 signaling in a dose- and time-dependent manner. Consistently, Hep3B cells lacking HS (EXT1-/-) show no hepcidin suppression in response to halofuginone. In vivo administration of halofuginone reduces hepcidin expression in an iron-overload mouse model (8.3 g/kg carbonyl iron). This effect was absent in mice with impaired liver HS sulfation (Ndst1f/fAlbCre+), confirming that halofuginone suppresses hepcidin via HSPG-mediated mechanisms. Additionally, halofuginone decreased hepcidin expression in mice subjected to acute inflammation. These findings establish halofuginone as a potential therapeutic for mitigating hepcidin-driven iron restriction in anemic disorders. Show less

Tissue fluidification and collective motility are pivotal in regulating embryonic morphogenesis, wound healing, and tumor metastasis. These processes frequently require that each cell constituent of a tissue coordinates its migration activity and directed motion through the oriented extension of lamellipodium cell protrusions, promoted by RAC1 activity. While the upstream RAC1 regulators in individual migratory cells or leader cells during invasion or wound healing are well characterized, how RAC1 is controlled in follower cells remains unknown. Here, we identify a MYO6-DOCK7 axis essential for spatially restricting RAC1 activity in a planar polarized fashion in model tissue monolayers. The MYO6-DOCK7 axis specifically controls the extension of cryptic lamellipodia required to drive tissue fluidification and cooperative-mode motion in otherwise solid and static carcinoma cell collectives. Show less

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease. Show less

Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism. Approach and Results: Overall, 37 patients and 28 healthy subjects were studied. Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry. The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay. The contribution of platelets to coagulation factor activity was selectively measured. Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22; Platelets in COVID-19 pneumonia are primed to spread proinflammatory and procoagulant activities in systemic circulation. Show less