Biology subjects

Tacconi, C.

Publications and source records attributed to Tacconi, C..

5 recordsLinked to original sources

bioRxiv2022

Metformin antiproliferative activity is exclusively mediated by the membrane functional expression of the Chloride Intracellular Channel 1 in glioblastoma stem cells

Metformin is the first-line drug for type-2 diabetes. Retrospective analyses, based on diabetic patients clinical data, demonstrate that daily assumption of metformin reduces the incidence of several kinds of solid tumors. Even though it is widely agreed that metformin must be internalized to accomplish its pharmacological activity, direct evidence about metformin membrane permeability and/or the presence of a specific membrane receptor in cancer cells is still missing. Here, we show that the transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) works as a privileged metformin receptor in glioblastoma stem-like cells. We found that metformin impairs tmCLIC1 activity by a specific binding coordinated by arginine 29. Its mutation, preventing metformin to bind and block tmCLIC1, abolishes the biguanide inhibition of glioblastoma cell proliferation in 2D and 3D models and metformin dependent effect on mitochondrial respiration. In addition, we demonstrate the direct binding between the drug and its target, and by in vivo experiments on zebrafish embryos and mice orthotopically engrafted with glioblastoma cells and treated with metformin, we prove that metformin binding to tmCLIC1 is crucial for metformin antineoplastic effect. Considering tmCLIC1s contribution to glioblastoma progression, the present work provides the fundaments for future development of strategies aimed at improving metformin-tmCLIC1 interaction to further increase metformin therapeutic potential.

cancer biology↗

bioRxiv2021

KIT is required for fetal liver erythropoiesis but dispensable for angiogenesis

Blood vessels are fundamental to sustain organ growth and tissue metabolism. In the mouse embryo, endothelial cell (EC) progenitors almost concomitantly give rise to the first blood vessels in the yolk sac and the large vessels of the embryo proper. Thereafter, the vascular network expands by angiogenesis to vascularize developing organs such as the brain. Although the first blood cells form in the yolk sac before blood vessels have assembled, consecutive waves of hematopoietic progenitors subsequently bud from hemogenic endothelium located within the wall of yolk sac and large intraembryonic vessels in a process termed endothelial to hematopoietic transition (endoHT). The receptor tyrosine kinase KIT is required for late embryonic erythropoiesis, but KIT is also expressed earlier in the hemogenic endothelium, in hematopoietic progenitors that arise via endoHT from hemogenic endothelium and non-hemogenic ECs, such as in the brain. However, it remains unclear whether KIT has essential roles in early hematopoiesis or even blood vessel growth. Here, we have combined transcriptomic analysis to delineate Kit expression with the analysis of knockout mice to show that KIT is expressed during but dispensable for yolk sac endoHT or brain angiogenesis but required for transient definitive erythropoiesis in the fetal liver.

developmental biology↗

bioRxiv2020

Lymphatic PD-L1 expression restricts tumor-specific CD8+ T cell responses

Lymph node (LN)-resident lymphatic endothelial cells (LECs) mediate peripheral tolerance by self-antigen presentation on MHC-I and constitutive expression of T cell inhibitory molecules, including PD-L1. Tumor-associated LECs also upregulate PD-L1 but the specific role of lymphatic PD-L1 in tumor immunity is not well understood. We generated a mouse model lacking lymphatic PD-L1 expression and challenged these mice with two orthotopic tumor models, B16F10 melanoma and MC38 colorectal carcinoma. Lymphatic PD-L1 deficiency resulted in a consistent expansion of tumor-specific CD8+ T cells in tumor-draining LNs in both tumor models, reduced primary tumor growth in the MC38 model, and increased the efficacy of adoptive T cell therapy in the B16F10 model. Strikingly, lymphatic PD-L1 primarily acted via apoptosis induction in tumor-specific CD8+ central memory T cells. Our findings demonstrate that LECs restrain tumor-specific immunity via PD-L1 and may explain why some cancer patients without PD-L1 expression in the tumor microenvironment still respond to PD-L1 / PD-1 targeting immunotherapy.

immunology↗

bioRxiv2020

LESR2 is a lymphatic endothelial-specific lncRNA that governs cell proliferation and migration through KLF4 and SEMA3C

Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determined, for the first time, the global lineage-specific lncRNAome of human dermal blood and lymphatic endothelial cells (BECs and LECs), combining RNA-Seq and CAGE-Seq. A subsequent genome-wide antisense oligonucleotide-knockdown screen of a robust set of BEC- and LEC-specific lncRNAs identified LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein, and phenotype rescue analyses revealed that LETR1 acts as a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides new evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.

genomics↗

bioRxiv2020

Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes

Lymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs, and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus have an unanticipated function in scavenging of modified LDL and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new insights into the diversity of LECs in murine lymph nodes and a rich resource for future studies into the regulation of immune responses by lymph node LECs.

immunology↗