Cell-cell Communication System Research Articles

Quorum sensing in Vibrio controls carbon metabolism to optimize growth in changing environmental conditions.

Bacteria sense population density via the cell-cell communication system called quorum sensing (QS). The evolution of QS and its maintenance or loss in mixed bacterial communities is highly relevant to understanding how cell-cell signaling impacts bacterial fitness and competition, particularly under varying environmental conditions such as nutrient availability. We uncovered a phenomenon in which Vibrio cells grown in minimal medium optimize expression of the methionine and tetrahydrofolate (THF) synthesis genes via QS. Strains that are genetically "locked" at high cell density grow slowly in minimal glucose media and suppressor mutants accumulate via inactivating-mutations in metF (methylenetetrahydrofolate reductase) and luxR (the master QS transcriptional regulator). In mixed cultures, QS mutant strains initially coexist with wild type, but as glucose is depleted, wild type outcompetes the QS mutants. Thus, QS regulation of methionine/THF synthesis is a fitness benefit that links nutrient availability and cell density, preventing accumulation of QS-defective mutants.

Imipenem exposure influence the expression of quorum sensing receptor sdiA in Escherichia coli.

The increasing trend of carbapenem resistance amongst Escherichia coli poses a major public health crisis and requires active surveillance of resistance mechanisms to control the threat. Quorum Sensing system plays a role in bacterial resistance to antibiotics. Quorum Sensing is a cell-cell communication system where bacteria alter their gene expression in response to specific stimuli. Here, in this study we investigated the transcriptional response of quorum sensing receptor, sdiA in E.coli under sub-inhibitory concentration of carbapenem in presence of quorum sensing signal molecules. Two E.coli isolates harbouring blaNDM were subjected to treatment with 10% SDS for 20 consecutive days of which blaNDM encoding plasmid was successfully eliminated from one isolate. Both the wild type and the cured mutant were then allowed to grow under eight different inducing conditions and the transcriptional response of sdiA gene was studied by quantitative real time PCR method. We found different response levels of sdiA in wild type and cured mutant under exogenous AHL and imipenem and when co-cultured with P.aeruginosa under imipenem stress. This study highlighted that sub-inhibitory concentration of imipenem in combination with AHL is acting as signal to SdiA, a quorum sensing receptor in E.coli.

A synthetic biology tool for contact-dependent synthetic cell communication.

Cell-cell communication and signal transduction through direct cell-cell contact are found ubiquitously in biology, with examples including T-cell activation upon contact formation with antigen-presenting cell in immunological synapses and electrical signal transduction in neuronal synapses. Despite the prevalence of intercellular communication at cell-cell interfaces, it is difficult to engineer and reconstitute functional proteins at membrane-membrane interfaces. A synthetic biology tool that can recapitulate signal transduction exclusively at membrane-membrane interfaces will be useful for designing synthetic intercellular communication pathways or providing a potential replacement for damaged and malfunctional natural cell-cell communication systems. Here, we present programmable activation of a split bioluminescent protein, NanoBiT, at the membrane-membrane interface between synthetic cells. We utilize a peptide-protein pair called SpyTag and SpyCatcher as adapter proteins to mediate functional reconstitution of NanoBiT. We illustrate an example of downstream protein activation through a designed light-based communication system by using a pair of photoactivatable proteins, iLID and SspB inside synthetic cells and demonstrate iLID-SspB dimerization triggered by reconstituted NanoBiT bioluminescence.

Host cell responses against the pseudomonal biofilm: A continued tale of host-pathogen interactions.

In biofilm formation, pathogens within the bacterial community coordinate a cell-cell communication system called quorum sensing (QS). This is achieved through various signalling pathways that regulate bacterial virulence and host immune response. Here, we reviewed the host responses, key clinical implications, and novel therapeutic approaches against the biofilms of P. aeruginosa. Given the high degree of intrinsic antibiotic resistance and biofilm formation by the pathogen, the ensuing treatment complications could result in high morbidity and mortality rates worldwide. Notwithstanding the availability of intervention strategies, there remains a paucity of effective therapeutic options to control biofilmogenesis. This review discusses the basic understanding of QS-associated virulence factors and several key therapeutic interventions to foil the biofilm menace of P. aeruginosa.

Distinct and redundant roles for zebrafish her genes during mineralization and craniofacial patterning.

The Notch pathway is a cell-cell communication system which is critical for many developmental processes, including craniofacial development. Notch receptor activation induces expression of several well-known canonical targets including those encoded by the hes and her genes in mammals and zebrafish, respectively. The function of these genes, individually and in combination, during craniofacial development is not well understood. Here, we used zebrafish genetics to investigate her9 and her6 gene function during craniofacial development. We found that her9 is required for osteoblasts to efficiently mineralize bone, while cartilage is largely unaffected. Strikingly, gene expression studies in her9 mutants indicate that although progenitor cells differentiate into osteoblasts at the appropriate time and place, they fail to efficiently lay down mineralized matrix. This mineralization role of her9 is likely independent of Notch activation. In contrast, her9 also functions redundantly with her6 downstream of Jagged1b-induced Notch activation during dorsoventral craniofacial patterning. These studies disentangle distinct and redundant her gene functions during craniofacial development, including an unexpected, Notch independent, requirement during bone mineralization.

Comparative genomic and functional analysis of Arthrobacter sp. UMCV2 reveals the presence of luxR-related genes inducible by the biocompound N, N-dimethylhexadecilamine.

Quorum sensing (QS) is a bacterial cell-cell communication system with genetically regulated mechanisms dependent on cell density. Canonical QS systems in gram-negative bacteria possess an autoinducer synthase (LuxI family) and a transcriptional regulator (LuxR family) that respond to an autoinducer molecule. In Gram-positive bacteria, the LuxR transcriptional regulators "solo" (not associated with a LuxI homolog) may play key roles in intracellular communication. Arthrobacter sp. UMCV2 is an actinobacterium that promotes plant growth by emitting the volatile organic compound N, N-dimethylhexadecylamine (DMHDA). This compound induces iron deficiency, defense responses in plants, and swarming motility in Arthrobacter sp. UMCV2. In this study, the draft genome of this bacterium was assembled and compared with the genomes of type strains of the Arthrobacter genus, finding that it does not belong to any previously described species. Genome explorations also revealed the presence of 16 luxR-related genes, but no luxI homologs were discovered. Eleven of these sequences possess the LuxR characteristic DNA-binding domain with a helix-turn-helix motif and were designated as auto-inducer-related regulators (AirR). Four sequences possessed LuxR analogous domains and were designated as auto-inducer analogous regulators (AiaR). When swarming motility was induced with DMHDA, eight airR genes and two aiaR genes were upregulated. These results indicate that the expression of multiple luxR-related genes is induced in actinobacteria, such as Arthrobacter sp. UMCV2, by the action of the bacterial biocompound DMHDA when QS behavior is produced.

The Proteomic and Transcriptomic Landscapes Altered by Rgg2/3 Activity in Streptococcus pyogenes.

Streptococcus pyogenes, otherwise known as Group A Streptococcus (GAS), is an important and highly adaptable human pathogen with the ability to cause both superficial and severe diseases. Understanding how S. pyogenes senses and responds to its environment will likely aid in determining how it causes a breadth of diseases. One regulatory network involved in GAS's ability to sense and respond to the changing environment is the Rgg2/3 quorum sensing (QS) system, which responds to metal and carbohydrate availability and regulates changes to the bacterial surface. To better understand the impact of Rgg2/3 QS on S. pyogenes physiology, we performed RNA-seq and tandem mass tag (TMT)-LC-MS/MS analysis on cells in which this system was induced with short hydrophobic peptide (SHP) pheromone or disrupted. Primary findings confirmed that pheromone stimulation in wild-type cultures is limited to the induction of operons whose promoters contain previously determined Rgg2/3 binding sequences. However, a deletion mutant of rgg3, a strain that endogenously produces elevated amounts of pheromone, led to extended alterations of the transcriptome and proteome, ostensibly by stress-induced pathways. Under such exaggerated pheromone conditions, a connection was identified between Rgg2/3 and the stringent response. Mutation of relA, the bifunctional guanosine tetra- and penta-phosphate nucleoside synthetase/hydrolase, and alarmone synthase genes sasA and sasB, impacted culture doubling times and disabled induction of Rgg2/3 in response to mannose, while manipulation of Rgg2/3 signaling modestly altered nucleotide levels. Our findings indicate that excessive pheromone production or exposure places stress on GAS resulting in an indirect altered proteome and transcriptome beyond primary pheromone signaling. IMPORTANCE Streptococcus pyogenes causes several important human diseases. This study evaluates how the induction or disruption of a cell-cell communication system alters S. pyogenes's gene expression and, in extreme conditions, its physiology. Using transcriptomic and proteomic approaches, the results define the pheromone-dependent regulon of the Rgg2/3 quorum sensing system. In addition, we find that excessive pheromone stimulation, generated by genetic disruption of the Rgg2/3 system, leads to stress responses that are associated with the stringent response. Disruption of stringent response affects the ability of the cell-cell communication system to respond under normally inducing conditions. These findings assist in the determination of how S. pyogenes is impacted by and responds to nontraditional sources of stress.

Discovery of Unannotated Small Open Reading Frames in Streptococcus pneumoniae D39 Involved in Quorum Sensing and Virulence Using Ribosome Profiling.

ABSTRACTStreptococcus pneumoniae, an opportunistic human pathogen, is the leading cause of community-acquired pneumonia and an agent of otitis media, septicemia, and meningitis. Although genomic and transcriptomic studies of S. pneumoniae have provided detailed perspectives on gene content and expression programs, they have lacked information pertaining to the translational landscape, particularly at a resolution that identifies commonly overlooked small open reading frames (sORFs), whose importance is increasingly realized in metabolism, regulation, and virulence. To identify protein-coding sORFs in S. pneumoniae, antibiotic-enhanced ribosome profiling was conducted. Using translation inhibitors, 114 novel sORFs were detected, and the expression of a subset of them was experimentally validated. Two loci associated with virulence and quorum sensing were examined in deeper detail. One such sORF, rio3, overlaps with the noncoding RNA srf-02 that was previously implicated in pathogenesis. Targeted mutagenesis parsing rio3 from srf-02 revealed that rio3 is responsible for the fitness defect seen in a murine nasopharyngeal colonization model. Additionally, two novel sORFs located adjacent to the quorum sensing receptor rgg1518 were found to impact regulatory activity. Our findings emphasize the importance of sORFs present in the genomes of pathogenic bacteria and underscore the utility of ribosome profiling for identifying the bacterial translatome.

The context-dependent, combinatorial logic of BMP signaling.

Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends on the complex way in which ligands are presented extracellularly and receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise bone morphogenetic protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on the competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems.

Dishonest Signaling in Microbial Conflicts.

Quorum sensing is a cell-cell communication system that bacteria use to express social phenotypes, such as the production of extracellular enzymes or toxins, at high cell densities when these phenotypes are most beneficial. However, many bacterial strains are known to lack a sensing mechanism for quorum signals, despite having the gene responsible for releasing the signals to the environment. The aim of this article is 2-fold. First, we utilize mathematical modeling and signaling theory to elucidate the advantage that a bacterial species can gain by releasing quorum signals, while not being able to sense them, in the context of ecological competition with a focal quorum sensing species, by reducing the focal species' ability to optimize the timing of expression of the quorum sensing regulated phenotype. Additionally, the consequences of such “dishonest signaling,” signaling that has evolved to harm the signal's receiver, on the focal quorum sensing species are investigated. It is found that quorum sensing bacteria would have to incur an additional, strategic, signaling cost in order to not suffer a reduction in fitness against dishonest signaling strains. Also, the concept of the Least Expensive Reliable Signal is introduced and applied to study how the properties of the regulated phenotype affect the metabolic investment in signaling needed by the quorum sensing bacteria to withstand dishonest signaling.

Molecular and Epigenetic Basis of Extracellular Vesicles Cell Repair Phenotypes in Targeted Organ-specific Regeneration.

Extracellular vesicles (EVs), which are released by most of the cells, constitute a new system of cell-cell communication by transporting DNA, RNA, and proteins in various vesicles namely exosomes, apoptotic bodies, protein complexes, high-density lipid (HDL) microvesicles, among others. To ensure accurate regulation of somatic stem cell activity, EVs function as an independent metabolic unit mediating the metabolic homeostasis and pathophysiological of several diseases such as cardiovascular diseases, metabolic diseases, neurodegenerative diseases, immune diseases, and cancer. Whist examining the EV biomolecules cargos and their microenvironments that lead to epigenetic alteration of the cell in tissue regeneration, studies have gained further insights into the biogenesis of EVs and their potential roles in cell biology and pathogenicity. Due to their small size, non-virulence, flexibility, and ability to cross biological barriers, EVs have promising therapeutic potentials in various diseases. In this review, we describe EV's mechanism of action in intercellular communication and transfer of biological information as well as some details about EVinduced epigenetic changes in recipient cells that cause phenotypic alteration during tissue regeneration. We also highlight some of the therapeutic potentials of EVs in organ-specific regeneration.

Carbon catabolite repression on the Rgg2/3 quorum sensing system in Streptococcus pyogenes is mediated by PTSMan and Mga.

Streptococcus pyogenes, also known as group A Streptococcus or GAS, is a human-restricted pathogen causing a diverse array of infections. The ability to adapt to different niches requires GAS to adjust gene expression in response to environmental cues. We previously identified the abundance of biometals and carbohydrates led to natural induction of the Rgg2/3 cell-cell communication system (quorum sensing, QS). Here we determined the mechanism by which the Rgg2/3 QS system is stimulated exclusively by mannose and repressed by glucose, a phenomenon known as carbon catabolite repression (CCR). Instead of carbon catabolite protein A, the primary mediator of CCR in Gram-positive bacteria; CCR of Rgg2/3 requires the PTS regulatory domain (PRD)-containing transcriptional regulator Mga. Deletion of Mga led to carbohydrate-independent activation of Rgg2/3 by down-regulatingrgg3, the QS repressor. Through phosphoablative and phosphomimetic substitutions within Mga PRDs, we demonstrated that selective phosphorylation of PRD1 conferred repression of the Rgg2/3 system. Moreover, given the carbohydrate specificity mediating Mga-dependent governance over Rgg2/3, we tested mannose-specific PTS components and found the EIIA/B subunit ManL was required for Mga-dependent repression. These findings provide newfound connections between PTSMan , Mga, and QS, and further demonstrate that Mga is a central regulatory nexus for integrating nutritional status and virulence.

Analysis and application of bacterial cell-cell communication system

Analysis and application of bacterial cell-cell communication system

Quorum sensing disruption regulates hydrolytic enzyme and biofilm production in estuarine bacteria.

Biofilms of heterotrophic bacteria cover organic matter aggregates and constitute hotspots of mineralization, primarily acting through extracellular hydrolytic enzyme production. Nevertheless, regulation of both biofilm and hydrolytic enzyme synthesis remains poorly investigated, especially in estuarine ecosystems. In this study, various bioassays, mass spectrometry and genomics approaches were combined to test the possible involvement of quorum sensing (QS) in these mechanisms. QS is a bacterial cell-cell communication system that relies notably on the emission of N-acylhomoserine lactones (AHLs). In our estuarine bacterial collection, we found that 28 strains (9%), mainly Vibrio, Pseudomonas and Acinetobacter isolates, produced at least 14 different types of AHLs encoded by various luxI genes. We then inhibited the AHL QS circuits of those 28 strains using a broad-spectrum lactonase preparation and tested whether biofilm production as well as β-glucosidase and leucine-aminopeptidase activities were impacted. Interestingly, we recorded contrasted responses, as biofilm production, dissolved and cell-bound β-glucosidase and leucine-aminopeptidase activities significantly increased in 4%-68% of strains but decreased in 0%-21% of strains. These findings highlight the key role of AHL-based QS in estuarine bacterial physiology and ultimately on biogeochemical cycles. They also point out the complexity of QS regulations within natural microbial assemblages.

Pyranoanthocyanins Interfering with the Quorum Sensing of Pseudomonas aeruginosa and Staphylococcus aureus.

Bacterial quorum sensing (QS) is a cell-cell communication system that regulates several bacterial mechanisms, including the production of virulence factors and biofilm formation. Thus, targeting microbial QS is seen as a plausible alternative strategy to antibiotics, with potentiality to combat multidrug-resistant pathogens. Many phytochemicals with QS interference activity are currently being explored. Herein, an extract and a compound of bioinspired origin were tested for their ability to inhibit biofilm formation and interfere with the expression of QS-related genes in Pseudomonas aeruginosa and Staphylococcus aureus. The extract, a carboxypyranoanthocyanins red wine extract (carboxypyrano-ant extract), and the pure compound, carboxypyranocyanidin-3-O-glucoside (carboxypyCy-3-glc), did not cause a visible effect on the biofilm formation of the P. aeruginosa biofilms; however, both significantly affected the formation of biofilms by the S. aureus strains, as attested by the crystal violet assay and fluorescence microscopy. Both the extract and the pure compound significantly interfered with the expression of several QS-related genes in the P. aeruginosa and S. aureus biofilms, as per reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results. Indeed, it was possible to conclude that these molecules interfere with QS at distinct stages and in a strain-specific manner. An extract with anti-QS properties could be advantageous because it is easily obtained and could have broad, antimicrobial therapeutic applications if included in topical formulations.

A novel anti-infective molecule nesfactin identified from sponge associated bacteria Nesterenkonia sp. MSA31 against multidrug resistant Pseudomonas aeruginosa

Overuse of antibiotics coupled with biofilm-forming ability has led to the emergence of multi-drug P. aeruginosa strains worldwide. Quorum sensing is a bacterial cell-cell communication system that regulates the expression of genes, including virulence factors, through production of acyl-homoserine lactones (AHLs) in Pseudomonas aeruginosa. The phenotypic expression of virulence factors in P. aeruginosa is mediated by quorum sensing systems (las and rhl). In this study an anti-infective molecule produced by a marine actinomycetes Nesterenkonia sp. MSA31 was elucidated as lipopeptide by NMR and LC-MS/MS analysis. The new lipopeptide molecule was named Nesfactin. This molecule effectively inhibited virulence phenotypes including production of hemolysin, protease, lipase, phospholipase, esterase, elastase, rhamnolipid, alginate, and pyocyanin, as well as motility and biofilm formation in P. aeruginosa. The high-performance thin layer chromatography (HPTLC) analysis revealed that the lipopeptide (50 μg/mL) inhibited production of the AHLs produced by the las and rhl quorum sensing systems (3-oxo-C12-HSL and C4-HSL, respectively). Docking analysis showed the binding affinity of the ligand towards the quorum sensing receptor molecules. The confocal laser scanning microscopy images showed the anti-biofilm effect of lipopeptide against P. aeruginosa. Nesfactin based hydrogel showed a significant antibiofilm effect on the catheter. This study suggests that the lipopeptide may be an effective anti-virulence treatment for Pseudomonas aeruginosa infections.

Cholesterol as a Second Messenger in the Hedgehog Signaling Pathway

The Hedgehog (HH) pathway is a cell-cell communication system essential for embryonic development; loss of proper HH signaling results in birth defects and cancer. Signaling is initiated when HH ligands are received on target cells by their receptor, Patched-1 (PTCH1). This relieves the inhibitory effect of PTCH1 on the G protein-coupled receptor Smoothened (SMO), allowing the HH signal to be transmitted across the membrane. The question of how PTCH1 inhibits SMO has remained a central mystery in developmental signaling for 25 years. Prior work implicated cholesterol as an endogenous lipid regulator of SMO. However, a major conundrum is presented by the abundance of cholesterol: how can a lipid that makes up 30%-50% of the plasma membrane be used to regulate a key signaling pathway? Using a custom CRISPR library focused on genes involved in lipid regulation, we asked the more general question of which lipids regulate HH signaling in target cells. We found that Sphingomyelin (SM) levels negatively regulate HH signaling. We show that SM exerts its effect by sequestering cholesterol into complexes, altering the chemical activity (or “accessibility”) of cholesterol. This highlights a key concept in membrane biology: only the accessible pool of cholesterol is available to interact with proteins and engage in signaling reactions. Using toxin-based sensors to measure accessible and sequestered cholesterol in cells, we find that HH ligands change cholesterol accessibility selectively in the membrane of the primary cilium. Primary cilia are antenna-like organelles required for HH signaling in all vertebrates. By compartmentalizing HH signaling in cilia, cells can use accessible cholesterol to communicate between PTCH1 and SMO without interfering with overall cellular cholesterol homeostasis. Our work suggests that the second messenger that communicates the signal between PTCH1 and SMO is the accessibility of cholesterol in a membrane compartment.

The Roles of Microbial Cell-Cell Chemical Communication Systems in the Modulation of Antimicrobial Resistance.

Rapid emergence of antimicrobial resistance (AMR) has become a critical challenge worldwide. It is of great importance to understand how AMR is modulated genetically in order to explore new antimicrobial strategies. Recent studies have unveiled that microbial communication systems, which are known to play key roles in regulation of bacterial virulence, are also associated with the formation and regulation of AMR. These microbial cell-to-cell chemical communication systems, including quorum sensing (QS) and pathogen–host communication mechanisms, rely on detection and response of various chemical signal molecules, which are generated either by the microbe itself or host cells, to activate the expression of virulence and AMR genes. This article summarizes the generic signaling mechanisms of representative QS and pathogen–host communications systems, reviews the current knowledge regarding the roles of these chemical communication systems in regulation of AMR, and describes the strategies developed over the years for blocking bacterial chemical communication systems in disease control. The research progress in this field suggests that the bacterial cell-cell communication systems are a promising target not only for disease control but also for curbing the problem of microbial drug resistance.

Engineering synthetic morphogen systems that can program multicellular patterning.

In metazoan tissues, cells decide their fates by sensing positional information provided by specialized morphogen proteins. To explore what features are sufficient for positional encoding, we asked whether arbitrary molecules (e.g., green fluorescent protein or mCherry) could be converted into synthetic morphogens. Synthetic morphogens expressed from a localized source formed a gradient when trapped by surface-anchoring proteins, and they could be sensed by synthetic receptors. Despite their simplicity, these morphogen systems yielded patterns reminiscent of those observed in vivo. Gradients could be reshaped by altering anchor density or by providing a source of competing inhibitor. Gradient interpretation could be altered by adding feedback loops or morphogen cascades to receiver cell response circuits. Orthogonal cell-cell communication systems provide insight into morphogen evolution and a platform for engineering tissues.

Abstract 683: Identification of a macrocyclic peptide that blocks the CD47-SIRPα interaction and its antitumor effect

Abstract Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. Immune checkpoint inhibitors, such as monoclonal antibodies (mAbs) to CTLA-4, PD-1, and PD-L1, have provided clinical benefit in patients with a variety of types of cancer, and a growing number of agents targeting immune checkpoints are in preclinical and clinical development. SIRPα is a transmembrane protein that is abundant in myeloid cells, such as macrophages and dendritic cells. SIRPα interacts with another transmembrane protein CD47 through their ectodomains, and they constitute the cell-cell communication system (the CD47-SIRPα system). We previously demonstrated that the interaction of SIRPα on macrophages with CD47 on tumor cells prevented the phagocytosis of tumor cells by macrophages. In contrast, blockage by anti-SIRPα antibodies of the CD47-SIRPα interaction enhanced the phagocytic activity of macrophages against antibody-opsonized tumor cells, suggesting that the CD47-SIRPα axis acts as an immune checkpoint pathway involved in tumor escape from immunosurveillance. Here, by the use of random nonstandard peptide integrated discovery (RaPID) system, we have identified novel macrocyclic peptides that bind to the extracellular domain of SIRPα with high affinity. These SIRPα-binding macrocyclic peptides inhibited the CD47-SIRPα interaction. Moreover, one of the SIRPα-binding macrocycles promoted the phagocytosis of antibody-opsonized tumor cells by macrophages in vitro and enhanced the antitumor effect of mAbs against tumor antigens in xenograft or syngeneic mouse models of cancer. Our results thus suggest that macrocyclic peptides against SIRPα hold promise as a novel tool for cancer immunotherapy. Citation Format: Daisuke Hazama, Yoji Murata, Takeshi Okamoto, Daisuke Tanaka, Mariko Sakamoto, Yuka Kakuchi, Yasuyuki Saito, Takenori Kotani, Yoshihiro Nishimura, Takashi Matozaki. Identification of a macrocyclic peptide that blocks the CD47-SIRPα interaction and its antitumor effect [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 683.