Tumor immune escape by autotaxin: keeping eosinophils at bay

Secreted autotaxin (ATX) promotes tumor progression by producing the pleiotropic lipid mediator lysophosphatidic acid (LPA). In a recent Nature Cancer paper, Bhattacharyya et al. show that ATX/LPA signaling suppresses CCL11-driven infiltration of eosinophils into the pancreatic tumor microenvironment to facilitate tumor progression, thus revealing a new ATX-mediated immune escape mechanism and highlighting the antitumor potential of eosinophil

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells.

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior

New Perspectives on the Role of Liquid Biopsy in Bladder Cancer: Applicability to Precision Medicine.

Bladder cancer (BC) is one of the most common tumors in the world. Cystoscopy and tissue biopsy are the standard methods in screening and early diagnosis of suspicious bladder lesions. However, they are invasive procedures that may cause pain and infectious complications. Considering the limitations of both procedures, and the recurrence and resistance to BC treatment, it is necessary to develop a new non-invasive methodology for early diagnosis and multiple evaluations in patients under follow-up for bladder cancer. In recent years, liquid biopsy has proven to be a very useful diagnostic tool for the detection of tumor biomarkers. This non-invasive technique makes it possible to analyze single tumor components released into the peripheral circulation and to monitor tumor progression. Numerous biomarkers are being studied and interesting clinical applications for these in BC are being presented, with promising results in early diagnosis, detection of microscopic disease, and prediction of recurrence and response to treatment

Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation.

GDE2 (also known as GDPD5) is a multispanning membrane phosphodiesterase with phospholipase D-like activity that cleaves select glycosylphosphatidylinositol (GPI)-anchored proteins and thereby promotes neuronal differentiation both in vitro and in vivo GDE2 is a prognostic marker in neuroblastoma, while loss of GDE2 leads to progressive neurodegeneration in mice; however, its regulation remains unclear. Here, we report that, in immature neuronal cells, GDE2 undergoes constitutive endocytosis and travels back along both fast and slow recycling routes. GDE2 trafficking is directed by C-terminal tail sequences that determine the ability of GDE2 to cleave GPI-anchored glypican-6 (GPC6) and induce a neuronal differentiation program. Specifically, we define a GDE2 truncation mutant that shows aberrant recycling and is dysfunctional, whereas a consecutive deletion results in cell-surface retention and gain of GDE2 function, thus uncovering distinctive regulatory sequences. Moreover, we identify a C-terminal leucine residue in a unique motif that is essential for GDE2 internalization. These findings establish a mechanistic link between GDE2 neuronal function and sequence-dependent trafficking, a crucial process gone awry in neurodegenerative diseases.This article has an associated First Person interview with the first author of the paper

Steroid Binding to Autotaxin Links Bile Salts and Lysophosphatidic Acid Signalling

Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs

Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor

Lysophosphatidic acid (LPA) is a new, intercellular signalling molecule in the brain that has an important role in adult hippocampal plasticity. Mice lacking the LPA1 receptor exhibit motor, emotional and cognitive alterations. However, the potential relationship among these concomitant impairments was unclear. Wild-type and maLPA1-null mice were tested on the hole-board for habituation and spatial learning. MaLPA1-null mice exhibited reduced exploration in a novel context and a defective intersession habituation that also revealed increased anxiety-like behaviour throughout the hole-board testing. In regard to spatial memory, maLPA1 nulls failed to reach the controls’ performance at the end of the reference memory task. Moreover, their defective working memory on the first training day suggested a delayed acquisition of the task’s working memory rule, which is also a long term memory component. The temporal interval between trials and the task’s difficulty may explain some of the deficits found in these mice. Principal components analysis revealed that alterations found in each behavioural dimension were independent. Therefore, exploratory and emotional impairments did not account for the cognitive deficits that may be attributed to maLPA1 nulls’ hippocampal malfunctio

Absence of LPA1 signaling results in defective cortical development

Lysophosphatidic acid (LPA) is a simple phospholipid with extracellular signaling properties mediated by specific G protein-coupled receptors. At least 2 LPA receptors, LPA(1) and LPA(2), are expressed in the developing brain, the former enriched in the neurogenic ventricular zone (VZ), suggesting a normal role in neurogenesis. Despite numerous studies reporting the effects of exogenous LPA using in vitro neural models, the first LPA(1) loss-of-function mutants reported did not show gross cerebral cortical defects in the 50% that survived perinatal demise. Here, we report a role for LPA(1) in cortical neural precursors resulting from analysis of a variant of a previously characterized LPA(1)-null mutant that arose spontaneously during colony expansion. These LPA(1)-null mice, termed maLPA(1), exhibit almost complete perinatal viability and show a reduced VZ, altered neuronal markers, and increased cortical cell death that results in a loss of cortical layer cellularity in adults. These data support LPA(1) function in normal cortical development and suggest that the presence of genetic modifiers of LPA(1) influences cerebral cortical development

Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior