Biology subjects

He, Y.

Publications and source records attributed to He, Y..

At least 433 records · Page 24Linked to original sources

bioRxiv2022

Droplet microfluidics forward for tracing target cells at single-cell transcriptome resolution

The rapid promotion of single-cell omics in various fields has begun to help solve many problems encountered in research including precision medicine, prenatal diagnosis, and embryo development. Meanwhile, single-cell techniques are also constantly updated with increasing demand. For some specific target cells, the workflow from droplet screening to single-cell sequencing is a preferred option, which also should reduce the impact of operation steps such as demulsification and cell recovery. We developed an all-in-droplet method integrating cell encapsulation, target sorting, droplet picoinjection, and single-cell transcriptome profiling on chips to achieve a labor-saving monitor of TCR-T cells. As a proof of concept, in this research, TCR-T cells were encapsulated, sorted, and performed single-cell transcriptome sequencing (scRNA-seq) by injecting reagents into droplet. It avoided the tedious operation of droplet breakage and re-encapsulation between droplet sorting and scRNA-seq. Moreover, convenient device operation will accelerate the progress of chip marketization. The strategy achieved an excellent recovery performance of single cell transcriptome with a median gene number over 4000 and a cross-contamination rate of 8.2 {+/-} 2%. Furthermore, this strategy allows us to develop a device with high integrability to monitor infused TCR-T cells, which will promote the development of adoptive T cell immunotherapy and their clinical application.

cell biology↗

bioRxiv2022

Heritability enrichment in context-specific regulatory networks improves phenotype-relevant tissue identification

Systems genetics holds the promise to decipher complex traits by interpreting their associated SNPs through gene regulatory networks derived from comprehensive multi-omics data of cell types, tissues, and organs. Here, we propose SpecVar to integrate paired chromatin accessibility and gene expression data into context-specific regulatory network atlas and regulatory categories, conduct heritability enrichment analysis with GWAS summary statistics, identify relevant tissues, and depict shared heritability and regulations by relevance correlation. Our method improves power upon existing approaches by associating SNPs with context-specific regulatory elements to assess heritability enrichments and by explicitly prioritizing gene regulations underlying relevant tissues. Experiments on GWAS of six phenotypes show that SpecVar can improve heritability enrichment, accurately detect relevant tissues, and reveal causal regulations. Furthermore, SpecVar correlates the relevance patterns for pairs of phenotypes and better reveals shared heritability and regulations of phenotypes than existing methods. Studying GWAS of 206 phenotypes in UK-Biobank demonstrates that SpecVar leverages the context-specific regulatory network atlas to prioritize phenotypes relevant tissues and shared heritability for biological and therapeutic insights. SpecVar provides a powerful way to interpret SNPs via context-specific regulatory networks and is available at https://github.com/AMSSwanglab/SpecVar.

genetics↗

bioRxiv2022

Estrogen signaling in the dorsal raphe regulates binge-like drinking in mice

The ovarian hormone estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms for estrogen-induced binge drinking are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We used the drinking in the dark (DID) behavioral test in mice to mimic binge drinking in humans. We found that female mice drank more alcohol than male mice in chronic DID tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor (ER) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling in binge alcohol drinking. In supporting this view, 5-HTDRN neurons from naive male mice had lower baseline neuronal firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naive female mice. Notably, this higher sensitivity was blunted by 17{beta}-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ER and ER{beta} are expressed in 5-HTDRN neurons, whereas ER agonist propyl pyrazole triol (PPT) depolarizes 5-HTDRN neurons and ER{beta} agonist diarylpropionitrile (DPN) hyperpolarizes 5-HTDRN neurons. Notably, both PPT and DPN treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, despite the fact that they have antagonistic effects on the activity dynamics of 5-HTDRN neurons. These results suggest that ERs inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ER- or ER{beta}-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ER/{beta} to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.

neuroscience↗

bioRxiv2022

Nucleotide and structural polymorphisms of the eastern oyster genome paint a mosaic of divergence, selection, and human impacts

The eastern oyster, Crassostrea virginica, is a valuable fishery and aquaculture species that provides critical services as an ecosystem engineer. Oysters have a life-history that promotes high genetic diversity and gene flow while also occupying a wide range of habitats in variable coastal environments from the southern Gulf of Mexico to the southern waters of Atlantic Canada. To understand the interplay of genetic diversity, gene flow, and intense environmental selection, we used whole genome re-sequencing data from 90 individuals across the eastern United States and Gulf of Mexico, plus 5 selectively bred lines. Our data confirmed a large phylogeographic break between oyster populations in the Gulf of Mexico and the Atlantic coast of the USA. We also demonstrated that domestication has artificially admixed genetic material between the two ocean basins, and selected lines with admixed ancestry continue to maintain heterozygosity at these sites through several generations post admixture, possibly indicating relevance to desirable aquaculture traits. We found that genetic and structural variation are high in both wild and selected populations, but we also demonstrated that, when controlling for domestication admixture across ocean basins, wild populations do have significantly higher levels of nucleotide diversity and copy number variation than selected lines. Within the Atlantic coast, we detected subtle but distinct population structure, introgression of selected lines within wild individuals, an interaction between structural variation and putatively adaptive population structure, and evidence of candidate genes responding to selection from salinity. Our study highlights the potential for applying whole genome sequencing to highly polymorphic species and provides a road map for future work examining the genome variation of eastern oyster populations.

evolutionary biology↗

bioRxiv2022

A computational framework linking synaptic adaptation to circuit behaviors in the early visual system

Retina ribbon synapses are the first synapses in the visual system. Unlike the conventional synapses in the central nervous system triggered by action potentials, ribbon synapses are uniquely driven by graded membrane potentials and are thought to transfer early sensory information faithfully. However, how ribbon synapses compress the visual signals and contribute to visual adaptation in retina circuits is less understood. To this end, we introduce a physiologically constrained module for the ribbon synapse, termed Ribbon Adaptive Block (RAB), and an extended "hierarchical Linear-Nonlinear-Synapse" (hLNS) framework for the retina circuit. Our models can elegantly reproduce a wide range of experimental recordings on synaptic and circuit-level adaptive behaviors across different cell types and species. In particular, it shows strong robustness to unseen stimulus protocols. Intriguingly, when using the hLNS framework to fit intra-cellular recordings from the retina circuit under stimuli similar to natural conditions, we revealed rich and diverse adaptive time constants of ribbon synapses. Furthermore, we predicted a frequency-sensitive gain-control strategy for the synapse between the photoreceptor and the CX bipolar cell, which differ from the classic contrast-based strategy in retina circuits. Overall, our framework provides a powerful analytical tool for exploring synaptic adaptation mechanisms in early sensory coding.

neuroscience↗

bioRxiv2022

A second unveiling: haplotig masking of the eastern oyster genome improves population-level inference

Genome assembly can be challenging for species that are characterized by high amounts of polymorphism, heterozygosity, and large effective population sizes. High levels of heterozygosity can result in genome mis-assemblies and a larger than expected genome size due to the haplotig versions of a single locus being assembled as separate loci. Here, we describe the first chromosome-level genome for the eastern oyster, Crassostrea virginica. Publicly released and annotated in 2017, the assembly has a scaffold N50 of 54 mb and is over 97.3% complete based on BUSCO analysis. The genome assembly for the eastern oyster is a critical resource for foundational research into molluscan adaptation to a changing environment and for selective breeding for the aquaculture industry. Subsequent resequencing data suggested the presence of haplotigs in the original assembly, and we developed a post hoc method to break up chimeric contigs and mask haplotigs in published heterozygous genomes and evaluated improvements to the accuracy of downstream analysis. Masking haplotigs had a large impact on SNP discovery and estimates of nucleotide diversity and had more subtle and nuanced effects on estimates of heterozygosity, population structure analysis, and outlier detection. We show that haplotig-masking can be a powerful tool for improving genomic inference, and we present an open, reproducible resource for the masking of haplotigs in any published genome.

genomics↗

bioRxiv2022

Cryo-EM complex structure of active GPR75 with a nanobody

Although there has been enormous progress in the last half-century in the drug discovery targeting obesity and associated co-morbidities, the clinical treatment of obesity remains tremendously challenging. GPR75 is an orphan receptor and is suggested to be a potential novel target for the control of obesity and related metabolic disorders. Inhibition of the GPR75 signaling pathway by small molecules, antibodies, or genetic manipulations may provide a therapeutic strategy for obesity. Here, we report the active-like Cryo-EM structure of human GPR75 with an intracellular nanobody, which reveals the receptor activation mechanism. The extensive interaction network required to achieve the active structure helps explain the allosteric coupling between the orthosteric pocket and the G-protein coupling domain. The well-defined orthosteric ligand binding pocket of human GPR75 provides a structural basis for anti-obesity drug discovery.

biophysics↗

bioRxiv2022

KAS-pipe2: a flexible toolkit for exploring KAS-seq and spKAS-seq data

Kethoxal-assisted ssDNA sequencing (KAS-seq) is gaining popularity as a robust and effective approach to study the dynamics of transcriptionally engaged RNA polymerases through profiling of genome-wide single-stranded DNA (ssDNA). Its latest variant, spKAS-seq, a strand-specific version of KAS-seq, has been developed to map genome-wide R-loop structures by detecting imbalances of ssDNA on two strands. However, user-friendly, open-source analysis pipelines for KAS-seq data are still lacking. Here we present KAS-pipe2 as a flexible and integrated toolkit to facilitate the analysis and interpretation of KAS-seq data. KAS-pipe2 can perform standard analyses such as quality control, read alignment, and differential RNA polymerase activity analysis. In addition, KAS-pipe2 introduces many novel features, including, but not limited to: calculation of transcriptional indexes, identification of single-stranded transcribing enhancers, and high-resolution mapping of R-loops. We use benchmark datasets to demonstrate that KAS-pipe2 provides a powerful framework to study transient transcriptional regulatory programs. KAS-pipe2 is available at https://github.com/Ruitulyu/KAS-pipe2.

bioinformatics↗

bioRxiv2022

Characterization of network hierarchy reflects cell-state specificity in genome organization

Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C datasets and derived the chromatin contact networks (CCNs). We discovered significant decreases in information transmission efficiencies in CCNs of colorectal cancer (CRC) and T-lineage acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Through network embedding in Poincare disk, the hierarchy depths of CCNs from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of CCN change was observed for the transition from embryo to differentiated primary tissues. During early embryo developments of both human and mouse, the hierarchy of embedded chromatin structure gradually establishes. Additionally, we found tissue-specific conservation of hierarchy order in normal CCNs, which was disturbed in tumor. Our findings uncover the cell-state related hierarchical characteristics in chromatin structure, which reveal chromatin loci that play important roles in stabilizing the cellular conditions.

bioinformatics↗

bioRxiv2022

Endothelial TIE1 restricts angiogenic sprouting to coordinate vein assembly in synergy with its homologue TIE2

ObjectiveVascular growth followed by vessel specification is crucial for the establishment of a hierarchical blood vascular network. We have here investigated mechanisms underlying venogenesis, particularly the molecular control over venous fate acquisition during vascular development. Approach and ResultsWe analyzed the function of TIE1 as well as its synergy with TIE2 in the regulation of vein formation by employing genetic mouse models targeting Tie1 and Tek. Cardinal vein growth appeared normal in TIE1 deficient mice, whereas TIE2 deficiency altered the identity of cardinal vein endothelial cells with the aberrant expression of DLL4. Interestingly, the parallel growth of murine cutaneous veins along with arteries, which was initiated at approximately embryonic day 13.5, was retarded in mice lack of TIE1. Tie1 deletion disrupted also venous integrity, displaying increased sprouting angiogenesis and vascular bleeding. Abnormal venous sprouts with defective arteriovenous alignment were also observed in the mesenteries of Tie1 deleted mice. Mechanistically, TIE1 deficiency resulted in the decreased expression of venous regulators including TIE2 while angiogenic regulators were upregulated. The alteration of TIE2 level by TIE1 insufficiency was further confirmed by the siRNA-mediated knockdown of Tie1 in cultured endothelial cells. Additionally, combining the endothelial deletion of Tie1 with one null allele of Tek resulted in a progressive increase of vein-associated angiogenesis leading to the formation of vascular tufts in retinas, whereas the loss of Tie1 alone produced only a relatively mild venous defect. ConclusionsFindings from this study imply that TIE1 and TIE2 act in a synergistic manner to restrict sprouting angiogenesis during vein formation.

developmental biology↗

bioRxiv2022

Development of Equine Polyclonal Antibodies as a Broad-Spectrum Therapy Against SARS-CoV-2 Variants

The Coronavirus disease 19 (COVID-19) pandemic has accumulated over 550 million confirmed cases and more than 6.34 million deaths worldwide. Although vaccinations has largely protected the population through the last two years, the effect of vaccination has been increasingly challenged by the emerging SARS-CoV-2 variants. Although several therapeutics including both monoclonal antibodies and small molecule drugs have been used clinically, high cost, viral escape mutations, and potential side effects have reduced their efficacy. There is an urgent need to develop a low cost treatment with wide-spectrum effect against the novel variants of SARS-CoV-2. Here we report a product of equine polyclonal antibodies that showed potential broad spectrum neutralization effect against the major variants of SARS-CoV-2. The equine polyclonal antibodies were generated by horse immunization with the receptor binding domain (RBD) of SARS-CoV-2 spike protein and purified from equine serum. A high binding affinity between the generated equine antibodies and the RBD was observed. Although designed against the RBD of the early wild type strain sequenced in 2020, the equine antibodies also showed a highly efficient neutralization capacity against the major variants of SARS-CoV-2, including the recent BA.2 Omicron variant (IC50 =1.867g/ml) in viral neutralization assay in Vero E6 cells using live virus cultured. The broad-spectrum neutralization capacity of the equine antibodies was further confirmed using pseudovirus neutralization assay covering the major SARS-CoV-2 variants including wild type, alpha, beta, delta, and omicron, showing effective neutralization against all the tested strains. Ex vivo reconstructed human respiratory organoids representing nasal, bronchial, and lung epitheliums were employed to test the treatment efficacy of the equine antibodies. Antibody treatment protected the human nasal, bronchial, and lung epithelial organoids against infection of the novel SARS-CoV-2 variants challenging public health, the Delta and Omicron BA.2 isolates, by reducing >95% of the viral load. The equine antibodies were further tested for potential side effects in a mouse model by inhalation and no significant pathological feature was observed. Equine antibodies, as a mature medical product, have been widely applied in the treatment of infectious diseases for more than a century, which limits the potential side effects and are capable of large scale production at a low cost. A cost-effective, wide-spectrum equine antibody therapy effective against the major SARS-CoV-2 variants can contribute as an affordable therapy to cover a large portion of the world population, and thus potentially reduce the transmission and mutation of SARS-CoV-2.

immunology↗

bioRxiv2022

Extrachromosomal DNA in the cancerous transformation of Barrett's esophagus

BACKGROUNDOncogenes are commonly amplified on extrachromosomal DNA (ecDNA) contributing to poor outcomes for patients. Currently, the chronology of ecDNA development is not known. We studied the origination and evolution of ecDNA in patients with Barretts esophagus (BE) who progressed to esophageal adenocarcinoma (EAC). METHODSWe analyzed whole-genome sequencing (WGS) data from a BE surveillance cohort and EAC patients at Cambridge University UK (n=206 patients). We also analyzed WGS data from biopsies taken at two time points from multiple sites in the esophagus from 80 patients enrolled in a case-control study at the Fred Hutchinson Cancer Center (FHCC) - 40 BE patients who progressed to EAC and 40 who did not. RESULTSecDNA was detected in 24% and 43% of BE patients with BE-associated early and late-stage EAC, respectively, in the Cambridge cross-sectional cohort. ecDNA was found in 33% of all FHCC BE patients who developed cancer, either prior to, or at EAC diagnosis. ecDNA was strongly associated with patients who developed cancer, in contrast with FHCC BE patients who did not progress (odds ratio, 18.8, CI - 2.3-152, p=3.3x10-4). ecDNAs were enriched for oncogenes and immunomodulatory genes and could be detected early in the transition from high-grade dysplasia to cancer and increased in copy number and complexity over time. CONCLUSIONSecDNAs can develop before a diagnosis of cancer in BE patients and are strongly selected for during the evolution to EAC. ecDNAs promote diverse oncogene and immunomodulatory gene amplification during EAC development and progression.

genomics↗

bioRxiv2022

Computational Enhanced Hi-C data reveals the function of structural geometry in genomic regulation

High-throughput chromosome conformation capture (Hi-C) technique profiles the genomic structure in a genome-wide fashion. The reproducibility and consistency of Hi-C data are essential in characterizing dynamics of genomic structures. We developed a diffusion-based method, CTG (Hi-C To Geometry), to deal with the technical bias induced by insufficient sampling in sequencing and obtain reliable gemeotric information of the chromatin. CTG properly quantifies dubiously weak or even undetected interactions and produces a consistent and reproducible framework for the 3D genomic structure. CTG allows for a reliable genome-wide insight on the alteration of genomic structures under different cellular conditions and reveals correlations between genomic-proximal genes at both transcriptional and translational levels. Cell-specific correspondence between gene-gene and corresponding protein-protein physical interactions, as well as that with the transcription correlation reveals the coordinated inter-molecular structural and regulatory information passage in the central dogma.

genomics↗

bioRxiv2022

Growth mindset promotes children's working memory performance through cortico-striatal interaction and fronto-parietal activation

Growth mindset--the belief that abilities are malleable through effort--drives motivation, action and achievement. Yet, the underlying mechanisms remain elusive, necessitating a unified framework that integrates cognitive, neural, and developmental processes. Leveraging longitudinal neuroimaging and computational modeling to reveal moment-to-moment decision responses and brain state dynamics during working memory (WM), we show that growth mindset enhances WM development from middle childhood to adolescence via nuanced cortico-striatal network dynamics that balance between brain state flexibility and stability. Behaviorally, children with higher growth mindset exhibited better WM performance both cross-sectionally and longitudinally, attributed to faster evidence accumulation during moment-to-moment information updating, especially under high task demands. Neurally, a higher growth mindset was associated with greater activation of the dorsal striatum, cingulo-opercular (action-mode), and fronto-parietal networks during WM, which further accounted for longitudinal WM improvement and latent evidence accumulation. Such cortico-striatal activation covaried with neurochemical mediators critical for motivation and executive functioning. Analyzing non-stationary network dynamics revealed that growth mindset optimized dynamical organization of cortico-striatal networks, with an activated state highly flexible to support moment-to-moment information updating and a deactivated state remaining stable across blocks to suppress irrelevant information. This suggests a balanced allocation of resources for accumulating evidence while suppressing noise during WM. Together, our findings support a neurocognitive framework in which growth mindset enhances WM development via nuanced orchestration of cortico-striatal networks to enable efficient dynamic computations and foster far-reaching cognitive development.

neuroscience↗

bioRxiv2022

BysR, a LysR-type Pleiotropic Regulator, Controls Production of Occidiofungin by Activating the LuxR-type transcriptional regulator AmbR1 in Burkholderia sp. JP2-270

Occidiofungin is a highly effective antifungal glycopeptide produced by certain Burkholderia strains. The ocf gene cluster directing occidiofungin biosynthesis is regulated by cluster-specific regulators encoded by ambR homolog(s) within the same gene cluster, while it remains unknown to what extent occidiofungin biosynthesis is connected with the core regulation network. Here, we report that a LysR-type regulator BysR acts as a pleotropical regulator, and is essential for occidiofungin biosynthesis by directly activating ambR1 transcription in Burkholderia sp. JP2-270. Deletion of bysR and ocfE both abolished the antifungal activity in JP2-270. This defect of the bysR mutant can be recovered by constitutively expressing bysR or ambR1 but not by ambR2. The EMSA assay collectively showed that BysR regulates ambR1 through direct binding to its promoter region. Taken together, occidiofungin produced by JP2-270 is the main substance inhibiting M. oryzae, and BysR controls occidiofungin production by directly activating the expression of ambR1. Besides, transcriptomic analysis revealed altered expression of 350 genes in response to bysR deletion, and the genes engaged in flagellar assembly and bacterial chemotaxis are the most enriched pathways. Also, 400 putative loci targeted by BysR were identified by DAP-seq in JP2-270. These loci not only include genes engaged in key metabolic pathways but also genes involved in secondary metabolic pathways. Collectively, we proposes that BysR may be a novel pleiotropic regulator, and ambR1 is an important target gene of BysR, which is an intra-cluster transcriptional regulatory gene that further activates the transcription of ocf gene cluster. IMPORTANCEThis study shows that BysR, a LysR-type transcriptional regulator (LTTR) from Burkholderia sp. JP2-270, activates the expression of ambR1 gene responsible for regulating the synthesis of occidiofungin. BysR also acts as a pleiotropic regulator that controls primary and secondary metabolism, antibiotic resistance, motility, transport and other cellular processes in Burkholderia sp. JP2-270. This study provides insight into the regulatory mechanism of occidiofungin synthesis and enhances our understanding of the regulatory patterns of the LysR-type regulator.

microbiology↗

bioRxiv2022

Six-Dimensional Single-Molecule Imaging with Isotropic Resolution using a Multi-View Reflector Microscope

We report a radially and azimuthally polarized multi-view reflector (raMVR) microscope for precise imaging of the 3D positions and 3D orientations of single molecules (SMs, 10.9 nm and 2.0{degrees} precisions using 5000 photons). These precisions are [~]1.5 times better than those of existing methods for SM orientation-localization microscopy. The raMVR microscope achieves 6D super-resolution imaging of Nile red (NR) molecules transiently bound to 150 nm, 350 nm, and 1 {micro}m-diameter lipid-coated spheres, accurately resolving their spherical morphology despite refractive-index mismatch. Simply by observing the rotational dynamics o raMVR images also resolve the infiltration of lipid membranes by amyloid-beta oligomers without covalent labeling. Finally, we demonstrate 6D imaging of HEK-293T cell membranes, where the orientations of merocyanine 540 molecules reveal heterogeneities in membrane fluidity. With its [~]2 {micro}m depth range, nearly isotropic 3D spatial resolution, and superior orientation measurement precision, we expect the raMVR microscope to enable 6D imaging of molecular dynamics within biological and chemical systems with unprecedented detail.

biophysics↗

bioRxiv2022

Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution

Spatially charting molecular cell types at single-cell resolution across the three-dimensional (3D) volume of the brain is critical for illustrating the molecular basis of the brain anatomy and functions. Single-cell RNA sequencing (scRNA-seq) has profiled molecular cell types in the mouse brain1, 2, but cannot capture their spatial organization. Here, we employed an in situ sequencing technique, STARmap PLUS3, 4, to map more than one million high-quality cells across the whole adult mouse brain and the spinal cord, profiling 1,022 genes at subcellular resolution with a voxel size of 194 X 194 X 345 nm in 3D. We developed computational pipelines to segment, cluster, and annotate 231 molecularly defined cell types and 64 tissue regions with single-cell resolution. To create a transcriptome-wide spatial atlas, we further integrated the STARmap PLUS measurements with a published scRNA-seq atlas1, imputing 11,844 genes at the single-cell level. Finally, we engineered a highly expressed RNA barcoding system to delineate the tropism of a brain-wide transgene delivery tool, AAV-PHP.eB5, 6, revealing its single-cell resolved transduction efficiency across the molecular cell types and tissue regions of the whole mouse brain. Together, our datasets and annotations provide a comprehensive, high-resolution single-cell resource that integrates a spatial molecular atlas, cell taxonomy, brain anatomy, and genetic manipulation accessibility of the mammalian central nervous system (CNS).

neuroscience↗

bioRxiv2022

Receptor for Hyaluronan-Mediated Motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients.

Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant metabolism and subsequent signaling of hyaluronan (HA). Hyaluronan Mediated Motility Receptor (RHAMM, HMMR) is a HA receptor that enables tumor cells to sense and respond to the TME during breast cancer progression. Focused gene expression analysis of an internal breast cancer patient cohort demonstrates increased RHAMM expression correlates with aggressive clinicopathological features. We also develop a 27-gene RHAMM-dependent signature (RDS) by intersecting differentially expressed genes in lymph node positive cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validate in an independent cohort. We demonstrate RDS predicts for poor survival and associates with invasive pathways. Further analyses using CRISPR/Cas9 generated RHAMM -/- breast cancer cells provide direct evidence that RHAMM promotes invasion in vitro and in vivo. Additional immunohistochemistry studies highlight heterogeneous RHAMM expression, and spatial transcriptomics confirms the RDS emanates from RHAMM-high invasive niches. We conclude RHAMM upregulation leads to the formation of invasive niches, which are enriched in RDS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes.

cancer biology↗