Patrick Legembre

Patrick Legembre
University of Limoges | UNILIM · Faculté de Médecine

PhD

About

137
Publications
25,804
Reads
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5,441
Citations
Introduction
By education, Patrick Legembre is an immunologist, who is now studying the role of death receptors and more specifically CD95/Fas on inflammation in Cancer such as triple negative breast cancer and auto-immune disorders including lupus. His team is designing original CD95 inhibitors to bring them to the patient bedside.
Additional affiliations
January 2020 - present
University of Limoges
Position
  • Managing Director
Description
  • I study CD95 and the non-apoptotic and pro-inflammatory functions of this death receptor. Also I develop therapeutic molecules targeting this receptor and its ligand CD95L.
January 2015 - December 2019
Centre Eugène Marquis
Position
  • Principal Investigator
Description
  • By targeting CD95/CD95L couple, we aim at developing novel immunotherapies against treat triple negative breast cancers.
June 2012 - present
La Ligue contre le cancer
Position
  • committee Member

Publications

Publications (137)
Article
Full-text available
Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here we report that serum levels of CD95L are higher in TNBC patients compared to other breast cancer patients. Metalloprotease-m...
Article
Full-text available
CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) pat...
Article
Full-text available
CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca²⁺ response via docking of PLCγ1 to the calcium-inducing domain (CID) within CD95. This signaling p...
Article
Full-text available
The death receptor CD95 plays a pivotal role in immune surveillance and immune tolerance. Binding of CD95L to CD95 leads to recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates caspase-8 and caspase-10. Efficient formation of the CD95/FADD/caspase complex, known as the death-inducing signaling comp...
Article
Full-text available
Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for bi...
Article
Full-text available
Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disea...
Article
Full-text available
Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take plac...
Article
Full-text available
Toxoplasma gondii infects approximately 1-2 billion people, and manipulation of the macrophage response is critical to host and parasite survival. A cleaved (cl)-CD95L form can promote cellular migration and we have previously shown that cl-CD95L aggravates inflammation and pathology in systemic lupus erythematosus (SLE). Findings have shown that C...
Article
Full-text available
Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaire...
Article
Full-text available
CD95 expression is preserved in triple-negative breast cancers (TNBCs) and CD95 loss in these cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2) using an unbi...
Article
Full-text available
The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. In different genetically engineered mouse models tumor expressed CD95 was shown to be critical for cell growth. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer (TNBC)...
Article
Although CD95L (also known as FasL) is still predominantly considered as a death ligand that induces apoptosis in infected and transformed cells, substantial evidence indicate that it can also trigger non-apoptotic signaling pathways whose pathophysiological roles remain to be fully elucidated. The transmembrane ligand CD95L belongs to the tumor ne...
Article
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T reg ) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interact...
Preprint
Full-text available
CD95L is expressed by tumor-infiltrating lymphocytes to eliminate CD95-expressing tumor cells and thereby CD95 loss by tumor cells is often considered as a consequence of an immunoediting process. Nonetheless CD95 expression is maintained in most triple negative breast cancers (TNBCs), and we recently reported that CD95 loss in TNBC cells triggers...
Preprint
Full-text available
The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. Stimulation by its cognate ligand CD95L on many cancer cells increases their growth, motility, ability to invade and/or their cancer stemness. Using genetically engineered mouse models of ovarian and liver cancer, we previously reported that deletion of CD95 in the tumor...
Article
Background Uterine transplant (UT) represents an opportunity to treat absolute uterine infertility. However, the use of uterine veins for venous return, in addition to ovarian veins, significantly increases the risk of ureteral wounds in the living donor and UT time for the recipient. Our aim was to demonstrate that dual ovarian venous return is su...
Article
Full-text available
CD95 is a pre-ligand-associated transmembrane (TM) receptor. The interaction with its ligand CD95L brings to a next level its aggregation and triggers different signaling pathways, leading to cell motility, differentiation or cell death. This diversity of biological responses associated with a unique receptor devoid of enzymatic property raises the...
Chapter
Apoptosis is a fundamental process contributing to tissue homeostasis, immune response, and development. CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNFR) superfamily. Its ligand, CD95L, was initially detected at the plasma membrane of activated T-lymphocytes and natural killer (NK) cells where it contributes to the el...
Article
Full-text available
The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLCγ1. Therefore, for the firs...
Article
Full-text available
Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. Im...
Article
Proceeding our effort to study protein-protein interaction between the death receptor CD95 and phospholipase PLCγ1, we present in the current work chameleon-like traits of peptidomimetic inhibitors. Minute analysis of the interaction suggests that most of the binding energy relies on van der Waals contacts rather than more specific features, such a...
Article
The death receptor CD95 (also known as Fas) induces apoptosis through protein/protein association and the formation of the death-inducing signaling complex. On the other hand, in certain biological conditions, this receptor recruits different proteins and triggers the formation of another complex designated motility-inducing signaling complex, whic...
Article
Full-text available
Staphylococcus aureus causes serious medical problems in human and animals. Here we show that S. aureus can compromise host genomic integrity as indicated by bacteria-induced histone H2AX phosphorylation, a marker of DNA double strand breaks (DSBs), in human cervix cancer HeLa and osteoblast-like MG-63 cells. This DNA damage is mediated by alpha ph...
Article
Full-text available
CD95 (also known as Fas) is the prototype of death receptors; however, evidence suggests that this receptor mainly implements non-apoptotic signaling pathways such as NF-κB, MAPK, and PI3K that are involved in cell migration, differentiation, survival, and cytokine secretion. At least two different forms of CD95 L exist. The multi-aggregated transm...
Article
Full-text available
Objective: The use of novel methods to characterize living tumor cells relies on well-conceived biobanks. Herein, we raised the question of whether the composition of fresh and freeze/thawed dissociated tumor samples is comparable in terms of quantitative and qualitative profiling. Results: Breast cancer is a heterogeneous disease, encompassing...
Article
Full-text available
Ruta chalepensis is a native herb of the Mediterranean region used in the traditional medicine of many countries. Phytochemical screening has shown the presence of bioactive molecules that are responsible for its pharmacological properties. The present study aimed at investigating the in vitro antioxidant and cytotoxic effect of volatile, ethanol a...
Article
Full-text available
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe str...
Article
Full-text available
CD95 (also known as Fas) is a member of the tumor necrosis factor receptor (TNFR) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Mutations in this receptor are associated with a loss of apoptotic signaling and have been detected in an autoimmune disorder called autoimmune lymphoproliferative syn...
Article
Full-text available
Ruta chalepensis is a native herb of the Mediterranean region used in the traditional medicine of many countries. Phytochemical screening has shown the presence of bioactive molecules that are responsible for its pharmacological properties. The present study aimed at investigating the in vitro antioxidant and cytotoxic effect of volatile, ethanol a...
Article
Full-text available
Endothelial cells lining new blood vessels that develop during inflammatory disorders or cancers act as doors that either allow or block access to the tumor or inflamed organ. Recent data show that these endothelial cells in cancer tissues and inflamed tissues of lupus patients overexpress CD95L, the biological role of which is a subject of debate....
Chapter
Full-text available
The receptor CD95 (also named Fas or APO-1) is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Mutations of this receptor or its ligand lead to autoimmune disorders such as systemic lupus erythematosus (SLE) and to cancers; hence, CD95 and CD...
Chapter
CD95 and its ligand CD95L play a major role in immune surveillance and homeostasis. CD95L is expressed by activated T lymphocytes and NK cells to induce apoptosis in cancer and virus-infected cells. The goal of this chapter is to describe a method used to immunoprecipitate CD95 and analyze its associated protein complex in cells stimulated with a c...
Chapter
Full-text available
Distribution of the death receptor CD95 into lipid rafts (aggregation) and/or its internalization may contribute to the implementation of the apoptotic signal at the detriment of the non-apoptotic signaling pathway [1–6]. Also CD95 can form different protein complexes via dynamic protein–protein interactions (PPIs) according to its interaction with...
Chapter
Full-text available
CD95 receptor, also called Fas or Apo-1, is a member of the tumor necrosis factor receptors (TNF-R) superfamily (Itoh and Nagata, J Biol Chem 268:10932-10937, 1993). Its cognate ligand, CD95L, is a transmembrane cytokine, which can be cleaved by metalloproteases (Matsuno et al., J Rheumatol 28:22-28, 2001; Vargo-Gogola et al., Arch Biochem Biophys...
Chapter
CD95 is a plasma membrane receptor that belongs to the TNF receptor family (Itoh and Nagata, J Biol Chem 268(15):10932-10937, 1993; Trauth et al., Science 245(4915):301-305, 1989). Accumulating evidence indicate that this so-called death receptor can also trigger non-apoptotic signaling pathways promoting inflammation and oncogenesis (Barnhart et a...
Book
This volume provides the most commonly used methods and protocols to study the apoptotic and non-apoptotic roles of CD95. Chapters explore molecular, biochemical, cellular methods and animal models to in order to better understand the biological functions of this cytokine. Written in the highly successful Methods in Molecular Biology series format,...
Article
Full-text available
TRAIL induces selective tumor cell death through TRAIL-R1 and TRAIL-R2. Despite the fact that these receptors share high structural homologies, induction of apoptosis upon ER stress, cell autonomous motility and invasion have solely been described to occur through TRAIL-R2. Using the TALEN gene-editing approach, we show that TRAIL-R1 can also induc...
Article
Full-text available
Two new compounds, cyaneodimycin (I) and cyaneomycin bearing a rare methacrylate residue, are isolated from cultures of the title bacterium associated with the marine lichen L.
Data
Isolated Th17 and Treg cells from two healthy donors were treated with or without 100 ng/mL cl-CD95L for 8 hr. Total RNA was extracted. Related to Figure 2.
Data
Relative n-fold change in the quantity of transcripts significantly (p ≤ 0.05) and differentially expressed in Th17 and Treg cells either unstimulated or stimulated with cl-CD95L (100 ng/mL). Data for each experimental group (n = 2 per condition) are shown. Related to Figure 2.
Article
Full-text available
Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca(2+) signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemin...
Article
Full-text available
CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) pat...
Article
Two new compounds, cyaneodimycin (1) and cyaneomycin (2) bearing a rare methacrylate residue, were isolated from cultures of the bacterium Streptomyces cyaneofuscatus associated with the marine lichen Lichina confinis. These astonishing structures may be derived from a pyruvate biosynthetic pathway. Cyaneodimycin (1) exhibited antiproliferative pro...
Article
Full-text available
Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways...
Article
Full-text available
Background: Constitutive activation of the PI3K/mTOR signaling pathway is observed in most, if not all, breast cancers. Accordingly, many PI3K and/or mTOR inhibitors have entered clinical trials, and completed studies should soon reveal the efficacy of these new drug families in the treatment of cancer patients. Objective: We present the PI3K/Ak...
Article
Full-text available
Cell Death Discovery, Published online: 12 October 2015; | doi:10.1038/cddiscovery.2015.1