The 2019 FASEB Science Research Conference on Lysophospholipid and Related Mediators: From Bench to Clinic, July 28 to August 2, 2019, Lisbon, Portugal

The FASEB Science Research Conference "Lysophospholipid and Related Mediators: From Bench to Clinic" conference was held in Lisbon, Portugal, from July 28 through August 2, 2019 as part of the FASEB 2019 Science Research Conference (SRC) series. The FASEB conference focused on current and emerging concepts related to bioactive lysophospholipids and their roles in health and disease, with emphasis on both the underlying biology of the signaling pathways and translation of work into drug development and clinical practice. Over the course of four and one-half days, 55 invited and 2 keynote speakers presented new and published work, supplemented with 48 posters. Given the availability and development of clinical therapeutics targeting their signaling pathways, sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) were the focus of many of the sessions, but other emerging bioactive lipid mediators were covered in several presentations. The FASEB conference also served as a platform for young and new investigators to chat one-on-one with senior principal investigators and professors on career development and advancement, mentoring, postdoctoral fellowships, and research in biopharma. A separate session by the participating women scientists addressed the role of women in basic, translational, and clinical research and development of drugs for women's health. The FASEB Science Research Conference series is an annual program of 30 to 40 conferences, held in different locations around the world. This FASEB conference has been a biennial event for 20 years, filling a unique and specific need in the field by providing a forum for interactions between basic scientists and clinical researchers. As an example, the immunomodulating drug fingolimod (Gilenya; Novartis, Basel, Switzerland), which targets S1P receptor signaling and is now U.S. Food and Drug Administration approved for the treatment of multiple sclerosis, was first reported at this FASEB conference in 2001. This year, attendees heard the promising results of early phase clinical trials of GLPG1690, an inhibitor of the lysophospholipase D autotaxin (ATX) that generates LPA, and the launch of the ISABELA phase 3 trial to study GLPG1690 in 1500 patients with idiopathic pulmonary fibrosis (IPF). Several presentations highlighted development of new and novel small molecule inhibitors targeting enzymes of S1P and LPA metabolism for therapy. The conference began with a keynote presentation by Dr. Jason Cyster (University of California, San Francisco, San Francisco, CA, USA), who was the first Tager Honored Speaker, a designation established at this year's conference as enduring recognition of Dr. Andrew Tager's contributions to the lysophospholipid field, in particular his identification of LPA signaling in IPF. Cyster's work has defined fundamental aspects of lymphocyte trafficking between tissue and blood in a S1P-regulated manner. His presentation included discussion on the identification of cell-type-specific S1P receptors, regulation of the receptors by the lymphocyte activation antigen CD69, and the identification of geranylgeranyl-l-glutathione as a novel ligand for the Gα13-coupled P2RY8 receptor that inhibits the migration and regulates growth of B cells (1). Following this, Dr. David Brindley (Fig. 1; University of Alberta, Edmonton, Alberta, Canada), recipient of the Journal of Lipid Research award, gave a keynote address on regulation of breast cancer by mammary adipose production of ATX and provided compelling evidence that the ATX/LPA signaling pathway is a regulator of maladaptive inflammation (2). The roles of S1P and LPA signaling and related molecules in solid tumors, metastasis, and hematologic malignancies were covered in talks, including ones by Sarah Spiegel (Virginia Commonwealth University, Richmond, VA, USA), Stuart Pitson (University of South Australia, Adelaide, South Australia, Australia), Julie Saba (University of California, San Francisco, Benioff Children's Hospital, San Francisco, CA, USA), and Gabor Tigyi (University of Tennessee Health Science Center, Memphis, TN, USA). Evidence from preclinical models supports regulation of the tumor microenvironment and immune system by these lipids and that targeting their production, receptors, or degradation pathways can elicit beneficial effects on tumor growth and metastasis. Both S1P and LPA have essential roles in vascular development, for example as evidenced by the embryonic lethality of mice with inherited deficiency of S1P receptor 1 (S1PR1) or ATX, and postnatally these lipids regulate inflammation, airway remodeling, and fibrosis. Tim Hla (Harvard Medical School/Boston Children's Hospital, Boston, MA, USA) discussed his group's work demonstrating crosstalk between S1PR1 and LPA receptor (LPAR) 1, whereby LPAR1 activation promotes heterodimerization of the receptors, recruits β arrestin to S1PR1, attenuates S1PR1 signaling, and increases lymphatic endothelial permeability to permit lymphocyte egress from lymph nodes (3). Activation of S1PR1 signaling in endothelium in the context of lung injury was discussed by Dolly Mehta (University of Illinois at Chicago, Chicago, IL, USA); the consequences of vascular S1P signaling in sepsis were the focus of work presented by Markus Gräler (Jena University Hospital, Jena, Germany); and Steven Dudek (University of Illinois at Chicago) provided additional information about the role of S1P signaling in pulmonary vasculature. Dr. Anantha Harijith, a neonatologist from the University of Illinois at Chicago, summarized his ongoing research related to sphingosine kinase 1 (SPHK1)/S1P/S1PR signaling in the development of bronchopulmonary dysplasia (BPD) and utility of the SPHK1 inhibitor PF-543 in BPD therapy. The requirement for ATX in vascular development was explained by Satoshi Ishii (Akita University, Akita, Japan), who demonstrated that LPAR4 and LPAR6 signal via Gα12/13 and Rho to activate Yes-associated protein, expression of Notch ligand δ-like 4, and angiogenesis (4). Novel roles for LPARs in lymphocyte trafficking were presented by both Wouter Moolenar's group (Netherlands Cancer Institute, Amsterdam, The Netherlands) and Junken Aoki (Tohoku University, Sendai, Japan). The role of ATX and LPA in allergen-challenged asthmatic airway inflammation in humans and a murine model of asthma was highlighted by Dr. Gye-Young Park of the University of Illinois at Chicago. Susan Schwab (New York University School of Medicine, New York, NY, USA) explained the roles of S1P/sphingolipid transporter 2 (Spns2) signaling and inflammation in the thymus, lymph nodes, spleen, and nonlymphoid tissues. L. Ashley Cowart (Virginia Commonwealth University) discussed sexual dimorphism in nonalcoholic fatty liver disease and the role of S1P in fibrosis. Andrea Huwiler (University of Bern) described TGF-β regulation of sphingosine kinases and S1P transport by SPNS2 in regulation of renal fibrosis. Andrew Morris (University of Kentucky, Lexington, KY, USA) discussed transcriptional circuits controlling expression of the phospholipid phosphatase 3 (PLLP3) gene encoding lipid phosphate phosphatase 3 (LPP3), which dephosphorylates bioactive lipids to limit vascular inflammation and atherosclerosis (5). Research into LPA and S1P signaling in diseases of the brain and nervous system was also presented. Jerold Chun (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA) described LPA-mediated hydrocephalus. Hiroshi Ueda (Kyoto University, Kyoto, Japan) described pain control by LPARs. Deron Herr (National University of Singapore, Singapore) reported on S1P regulation of neuropathy. Diana Escalante-Alcalde (National Autonomous University of Mexico, Mexico City, Mexico) presented research on the role in the adult brain of LPP3, which degrades and inactivates LPA, S1P, and related molecules. Exciting findings about the basic biology of the S1P and LPA signaling systems were also introduced. Discovery of a second membrane-associated S1P transporter protein, major facilitator superfamily domain containing 2B (Mfsd2b), which functions to export S1P from red blood cells and platelets (6), was presented by Nam Long Nguyen (National University of Singapore). Kevin Lynch (University of Virginia, Charlottesville, VA, USA) described his group's work to develop screening systems for S1P transport inhibitors, optimization of lead compounds, and testing in preclinical models. Similarly stimulating work from Anastassi Perrakis' group (Netherlands Cancer Institute) detailed structure and function of the active site, hydrophobic pocket, and tunnel within ATX that are differentially affected by type 1–4 ATX inhibitors and delivery of LPA by ATX that is blocked by type 4 inhibitors, such as GLPG1690. Jerold Chun also provided insight gained from crystal structures of the LPARs and receptor-binding parameters determined by backscattering interferometry (7). In summary, the FASEB conference provided a unique forum for multidisciplinary scientists within the field to share latest research findings on the receptors enzymes regulating lysophospholipid production, metabolism, and transport and to discuss potential therapeutic targets to diagnose, prevent, or treat disease. The meeting facilitated interactions between early career and young investigators with established scientists via presentations and interactive career workshops. A robust and well-attended women in science session provided a platform to promote inclusivity in the field and a forum to share best practices for success in science. The conference organizer recognizes the generous support of the following sponsors (in alphabetical order): Avanti Polar Lipids; Biochimica et Biophysica Acta (BBA)–Molecular and Cell Biology of Lipids; British Pharmacological Society; Cancers, an open access journal by MDPI; Cayman Chemical; Celgene; Galápagos; International Journal of Molecular Sciences, an open access journal by MDPI; Journal of Biological Chemistry (JBC); Journal of Cell Biology (JCB); Journal of Lipid Research (JLR); U.S. National Institutes of Health, National Cancer Institute (NIH-NCI); The Sphingolipid Club; and the University of Kentucky, Gill Heart and Vascular Institute. Additionally, the auhors thank Dr. David Ebenezer for outstanding audiovisual assistance. The conference was supported by NCI grant R13CA239619.

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