Biology subjects

Zhao, L.

Publications and source records attributed to Zhao, L..

At least 289 records · Page 16Linked to original sources

bioRxiv2021

Extrachromosomal DNA is associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma

Extrachromosomal DNA plays an important role in oncogene amplification in tumour cells and poor outcomes across multiple cancers. However, the function of extrachromosomal DNA in gastric cardia adenocarcinoma (GCA) is very limited. Here, we investigated the availability and function of extrachromosomal DNA in GCA from a Chinese cohort of GCA using whole-genome sequencing (WGS), whole-exome sequencing (WES), and immunohistochemistry. For the first time, we identified the ecDNA amplicons present in most GCA patients, and found that some oncogenes are present as ecDNA amplicons in these patients. We found that oncogene ecDNA amplicons in the GCA cohort were associated with the chromothripsis process and may be induced by accumulated DNA damage due to local dietary habits in the geographic region. Strikingly, we observed diverse correlations between the presence of ecDNA oncogene amplicons and prognosis, where ERBB2 ecDNA amplicons correlated with good prognosis, EGFR ecDNA amplicons correlated with poor prognosis, and CCNE1 ecDNA amplicons did not correlate with prognosis. Large-scale ERBB2 immunohistochemistry results from 1668 GCA patients revealed that there was a positive correlation between the presence of ERBB2 and prognosis in 2-7-year survival; however, there was a negative correlation between the presence of ERBB2 and prognosis in 0-2-year survival. Our observations indicate that the presence of ERBB2 ecDNA in GCA patients may represent a good prognosis marker.

genomics↗

bioRxiv2021

Connectome-based model predicts individual psychopathic traits in college students

BackgroundPsychopathic traits have been suggested to increase the risk of violations of socio-moral norms. Previous studies revealed that abnormal neural signatures are associated with elevated psychopathic traits; however, whether the intrinsic network architecture can predict psychopathic traits at the individual level remains unclear. MethodsThe present study utilized connectome-based predictive modeling (CPM) to investigate whether whole-brain resting-state functional connectivity (RSFC) can predict psychopathic traits in the general population. RS functional magnetic resonance imaging data were collected from 84 college students with varying psychopathic traits measured by the Levenson Self-Report Psychopathy Scale (LSRP). ResultsWe found that RSFC of the negative networks predicted individual differences in total LSRP and secondary psychopathy scores but not primary psychopathy score. Particularly, nodes with the most connections in the predictive connectome anchored in the prefrontal cortex (e.g., anterior prefrontal cortex and orbitofrontal cortex) and limbic system (e.g., anterior cingulate cortex and insula). In addition, the connections between the occipital network (OCCN) and cingulo-opercular network (CON) served as a significant predictive connectome for total LSRP and secondary psychopathy score. ConclusionCPM constituted by whole-brain RSFC significantly predicted psychopathic traits individually in the general population. The prefrontal cortex and limbic system at the anatomic level and the CON and OCCN at the functional network level plays a special role in the predictive model--reflecting atypical executive control and affective processing for individuals with elevated psychopathic traits. These findings may provide some implications for early detection and potential intervention of psychopathic tendency.

neuroscience↗

bioRxiv2021

Structural organization of the C1b projection within the ciliary central apparatus

9+2 motile cilia contain 9 doublet microtubules and a central apparatus (CA) composed of two singlet microtubules with associated projections. The CA plays crucial roles in regulating ciliary motility. Defects in CA assembly or function usually result in motility-impaired or paralyzed cilia, which in humans causes disease. Despite their importance, the protein composition and functions of most CA projections remain largely unknown. Here, we combined genetic approaches and quantitative proteomics with cryo-electron tomography and subtomogram averaging to compare the CA of wild-type Chlamydomonas with those of two CA mutants. Our results show that two conserved proteins, FAP42 and FAP246, are localized to the L-shaped C1b projection of the CA. We also identified another novel CA candidate protein, FAP413, which interacts with both FAP42 and FAP246. FAP42 is a large protein that forms the peripheral beam of the C1b projection, and the FAP246-FAP413 subcomplex serves as the bracket between the beam (FAP42) and the C1b pillar that attaches the projection to the C1 microtubule. The FAP246-FAP413-FAP42 complex is essential for stable assembly of both the C1b and C1f projections, and loss of any of these proteins leads to ciliary motility defects. Our results provide insight into the subunit organization and 3D structure of the C1b projection, suggesting that the FAP246-FAP413-FAP42 subcomplex is part of a large interconnected CA-network that provides mechanical support and may play a role in mechano-signaling between the CA and radial spokes to regulate dynein activity and ciliary beating. Summary StatementThe present work provides insight into the subunit organization and 3D structure of the C1b projection of CA and the mechanism by which it regulates dynein activity and ciliary beating.

cell biology↗

bioRxiv2021

Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2

The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here we report the cryo-electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric Gs protein at a global resolution of 2.8 [A]. The structure reveals that TIP39 adopts a unique loop conformation at N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane (TM) domain. Molecular dynamics (MD) simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide (PTHrP). We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs, but also offer a foundation to systematically rationalize the available pharmacological data to develop novel therapies for various disorders associated with PTH2R.

biochemistry↗

bioRxiv2021

Characterization of the consensus mucosal microbiome of colorectal cancer

Recent evidence suggests that dysbiosis, an imbalance of microbiota, is associated with increased risk of colorectal cancer. Diverse microbial organisms are physically associated with the cells found in tumor biopsies. Characterizing this mucosa-associated microbiome through genome sequencing has advantages compared to culture-based profiling. However, there are notable challenges in accurately characterizing the features of tumor microbiomes with methods like transcriptome sequencing. Most sequence reads originate from the host. Moreover, there is a high likelihood of bacterial contaminants being introduced. Another major challenge is the microbiome diversity among different studies. Colorectal tumors demonstrate a significant extent of microbiome variation among individuals from different geographic and ethnic origins. To address these challenges, we identified a consensus microbiome for colorectal cancer through analyzing 924 tumors from eight independent RNA-Seq data sets. A standardized meta-transcriptomic analysis pipeline was established and applied to the complete CRC cohort. Common contaminants were filtered out. Our study involved taxonomic investigation of non-human sequences, linked microbial signatures to phenotypes and the association of microbiome with tumor microenvironment components. Microbiome profiles across different CRC cohorts were compared, and recurrently altered microbial shifts specific to CRC were determined. We identified cancer-specific set of 114 microbial species associated with tumors that were found among all investigated studies. Validating our approach, we found that Fusobacterium nucleatum was one of the most enriched bacterial species in CRC. Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria were among the four most abundant phyla for CRC microbiome. Signficant associations between the consensus species and specific immune cell types were noted. Our results are available as a web data resource for other researchers to explore (https://crc-microbiome.stanford.edu).

genomics↗

bioRxiv2021

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer the structural basis of ago-allosterism at GLP-1R and new knowledge to design better therapeutics.

molecular biology↗

bioRxiv2021

Flexibility-aware graph-based algorithm improves antigen epitopes identification

Epitopes of an antigen are the surface residues in the spatial proximity that can be recognized by antibodies. Identifying such residues has shown promising potentiality in vaccine design, drug development and chemotherapy, thus attracting extensive endeavors. Although great efforts have been made, the epitope prediction performance is still unsatisfactory. One possible issue accounting to this poor performance could be the ignorance of structural flexibility of antigens. Flexibility is a natural characteristic of antigens, which has been widely reported. However, this property has never been used by existing models. To this end, we propose a novel flexibility-aware graph-based computational model to identify epitopes. Unlike existing graph-based approaches that take the static structures of antigens as input, we consider all possible variations of the side chains in graph construction. These flexibility-aware graphs, of which the edges are highly enriched, are further partitioned into subgraphs by using a graph clustering algorithm. These clusters are subsequently expanded into larger graphs for detecting overlapping residues between epitopes if exist. Finally, the expanded graphs are classified as epitopes or non-epitopes via a newly designed graph convolutional network. Experimental results show that our flexibility-aware model markedly outperforms existing approaches and promotes the F1-score to 0.656. Comparing to the state-of-the-art, our approach makes an increment of F1-score by 16.3%. Further in-depth analysis demonstrates that the flexibility-aware strategy contributes the most to the improvement. The source codes of the proposed model is freely available at https://github.com/lzhlab/epitope. Author summaryEpitope prediction is helpful to many biomedical applications so that dozens of models have been proposed aiming at improving prediction efficiency and accuracy. However, the performances are still unsatisfactory due to its complicated nature, particularly the noteworthy flexible structures, which makes the precise prediction even more challenging. The existing approaches have overlooked the flexibility during model construction. To this end, we propose a graph model with flexibility heavily involved. Our model is mainly composed of three parts: i) flexibility-aware graph construction; ii) overlapping subgraph clustering; iii) graph convolutional network-based subgraph classification. Experimental results show that our newly proposed model markedly outperforms the existing best ones, making an increment of F1-score by 16.3%.

bioinformatics↗

bioRxiv2021

Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19

Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon in vitro stimulation. Correlating clinical features to the ability of plasma from COVID-19 patients to stimulate control platelets identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the Fc{gamma}RIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions, thus identifying these potentially actionable pathways as central for platelet activation and/or vascular complications in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect. These studies have implications for the role of platelet hyperactivation in complications associated with SARS-CoV-2 infection. Cover illustration O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY One-sentence summaryThe Fc{gamma}RIIA and C5a-C5aR pathways mediate platelet hyperactivation in COVID-19

immunology↗

bioRxiv2021

Integrative analysis of the hydroxypyruvate reductases revealing their distinct roles in photorespiration of Chlamydomonas

Photorespiration plays an important role in maintaining normal physiological metabolism in higher plants and other oxygenic organisms such as algae. The unicellular eukaryotic organism Chlamydomonas is reported to have a different photorespiration system from that in higher plants, and only two out of nine genes encoding photorespiratory enzymes have been experimentally characterized. Hydroxypyruvate reductase (HPR), which is responsible for the conversion of hydroxypyruvate into glycerate, is poorly understood and not yet explored in Chlamydomonas. To identify the candidate genes encoding hydroxypyruvate reductase in Chlamydomonas (CrHPR) and uncover their elusive functions, we performed sequence comparison, enzyme activity measurement, subcellular localization, and analysis of knockout/knockdown strains. Together we identify five proteins to be good candidates as CrHPRs, all of which are detected with the activity of hydroxypyruvate reductase. CrHPR1, a NADH-dependent enzyme in mitochondria, may function as the major component of photorespiration, and deletion of CrHPR1 causes severe photorespiratory defects. CrHPR2 takes parts in the cytosolic bypass of photorespiration as the compensatory pathway of CrHPR1 for the reduction of hydroxypyruvate. CrHPR4, with NADH as the cofactor, may participate in photorespiration by acting as the chloroplastidial glyoxylate reductase in glycolate-quinone oxidoreductase system. Therefore, our results reveal that the CrHPRs are far more complex than previously recognized, and provide a greatly expanded knowledge base for studies to understand how CrHPRs perform their functions in photorespiration. These will facilitate the genetic engineering for crop improvement by synthetic biology. Brief summaryIdentification and characterization of genes encoding hydroxypyruvate reductases in Chlamydomonas, demonstrating difference in the enzymatic activity, subcellular location, as well as function in photorespiration.

plant biology↗

bioRxiv2021

Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites

Precocious puberty (PP) mostly stems from endocrine disorders. However, its triggering factors, especially for the early onset of partial PP, and the associated pathogenic mechanisms remain ambiguous. In this study, a systematic analysis in the form of a questionnaire of lifestyles, gut microbiome, and serum metabolome data was carried out to examine the pathogenesis of PP in a cohort comprised of 200 girls, with or without PP. The analysis revealed substantial alterations in gut microbiota, serum metabolites, as well as lifestyle patterns in the PP group, which were characterized by an elevated abundance of {beta}-glucuronidase-producing and butyrate-producing bacteria, and excessive lipid concentration with decreased levels of organic nitrogen compounds in the serum of the participants. These differential microbes and metabolites tend to be reliable non-invasive diagnostic biomarkers aiding the early diagnosis of PP and exhibit a strong discriminative power (AUC = 0.93 and AUC = 0.97, respectively). Furthermore, the microbial biomarkers were confirmed in an independent validation cohort (n = 83, AUC = 0.85). Moreover, structural equation modeling revealed that unhealthy dietary habits were the primary contributors for the alteration of gut microbiota and serum metabolites, triggering the imbalance in the host hormones that leads to premature physical development. Our study determines a causal relationship among the gut microbiota, host metabolites, diet, and clinical characteristics of preadolescent girls who experienced early onset of PP, and formulates non-invasive diagnostic tools demonstrating excellent performance for the early detection of PP.

microbiology↗

bioRxiv2021

Transcriptome-based phylogeny and whole-genome duplication in Theaceae

Theaceae, with three tribes and nine genera, is a family of great economic and ecological importance. Recent phylogenetic analyses based on plastid genome resolved the relationship among three tribes and the intergeneric relationships within Gordonieae and Stewartieae. However, generic level relationships within the largest tribe Theeae were not fully resolved and potential hybridization among genera within Theeae revealed previously also remains to be tested further. Here we conducted a comprehensive phylogenomic study of Theaceae based on transcriptomes and low-depth whole-genome sequencing of 57 species as well as additional plastome sequence data from previous work. Phylogenetic analyses suggested that Stewartieae was the first-diverging clade in Theaceae, consistent with previous study using plastomic data. Within Theeae, the highly supported Apterosperma-Laplacea clade grouped with Pyrenaria with maximum support based on the partitioned and unpartitioned concatenation analyses using the 610 low-copy nuclear genes, leaving Camellia and Polyspora as another sister genera in the tribe. PhyloNet analyses suggested one reticulation event within Camellia and Pyrenaria respectively, but no intergeneric reticulations were detected in Theeae. Another introgression was found between Gordonia lasianthus and the common ancestor of Gordonieae during the Late Oligocene. The existing land bridges (e.g. Bering land bridge) might have facilitated this ancient introgression. Further researches need to be conducted to uncover the interspecific introgression pattern within Camellia. Ks distribution analyses supported the tea family shared one whole-genome duplication (WGD) event Ad-{beta}, which was recently mapped to the clade containing core Ericales, Primuloids, Polemonioids and Lecythidaceae.

evolutionary biology↗

bioRxiv2021

A spatial and cellular distribution of neurotropic virus infection in the mouse brain revealed by fMOST and single cell RNA-seq

Neurotropic virus infection can cause serious damage to the central nervous system (CNS) in both human and animals. The complexity of the CNS poses unique challenges to investigate the infection of these viruses in the brain using traditional techniques. In this study, we explore the use of fluorescence micro-optical sectioning tomography (fMOST) and single cell RNA sequencing (scRNA-seq) to map the spatial and cellular distribution of a representative neurotropic virus, rabies virus (RABV), in the whole brain. Mice were inoculated with a lethal dose of recombinant RABV expressing enhanced green fluorescent protein (EGFP) under different infection routes, and a three-dimensional view of the distribution of RABV in the whole mouse brain was obtained using fMOST. Meanwhile, we pinpointed the cellular distribution of RABV by utilizing scRNA-seq. Our fMOST data provide the first evidence that RABV can infect multiple nuclei related to fear independent of different infection routes. More surprisingly, scRNA-seq data indicate that besides neurons RABV can infect macrophages and NK cells in vivo. Collectively, this study draws a comprehensively spatial and cellular map of RABV infection in the mouse brain, providing a novel and insightful strategy to investigate the pathogenesis of neurotropic viruses.

microbiology↗

bioRxiv2021

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a Gs heterotrimer at a global resolution of 2.9 [A]. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C-terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.

molecular biology↗

bioRxiv2021

A tandem-repeat dimeric RBD protein-based COVID-19 vaccine ZF2001 protects mice and nonhuman primates

A safe, efficacious and deployable vaccine is urgently needed to control COVID-19 pandemic. We report here the preclinical development of a COVID-19 vaccine candidate, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and NHPs, and also elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 g or 50 g ZF2001 prevented infection with SARS-CoV-2 in lung, trachea and bronchi, with milder lung lesions. No evidence of disease enhancement is observed in both models. ZF2001 is being evaluated in the ongoing international multi-center Phase 3 trials (NCT04646590) and has been approved for emergency use in Uzbekistan.

immunology↗

bioRxiv2021

Mapping Complex Brain Torque Components and Their Genetic and Phenomic Architecture in 24,112 healthy individuals

The mechanisms determining the development and individual variability of brain torque (BT) remain unclear. Here, all relevant components of BT were analyzed using neuroimaging data of up to 24,112 individuals from 6 cohorts. Our large-scale data confirmed the population-level predominance of the typical anticlockwise torque and suggested a "first attenuating, then enlarging" dynamic across the lifespan primarily for frontal, occipital and perisylvian BT features. Sex/handedness differences in BT were found and were related to cognitive sex/handedness differences in verbal-numerical reasoning. We observed differential heritability of up to 56% for BT, especially in temporal language areas, and identified numerous genome- and phenome-wide significant associations pointing to neurodevelopment, cognitive functions, lifestyle, neurological and psychiatric disorders, sociodemographic, cardiovascular and anthropometric traits. This study provides a comprehensive description of BT and insights into biological and other factors that may contribute to the development and individual variations of BT.

neuroscience↗

bioRxiv2021

Genome Size Estimation and Full-length Transcriptome of Sphingonotus tsinlingensis: Genetic Background for the Drought-Adapted Grasshopper

Sphingonotus Fieber, 1852 (Orthoptera: Acrididae) is a species-rich grasshopper genus with ~146 species. All species of this genus prefer dry environments, such as: desert, steppe, sand, and stony benchland. This genomic study aimed to understand the evolution and ecology of these grasshopper species. Here, the genome size of Sphingonotus tsinlingensis was estimated using flow cytometry and the first high-quality full-length transcriptome of this species is presented, which may serve as a reference genetic resource for the drought-adapted grasshopper species of Sphingonotus Fieber. The genome size of Sphingonotus tsinlingensis was ~12.8 Gb. Based on the 146.98 Gb Pacbio isoform sequencing data, 221.47 Mb full-length transcripts were assembled. Among these transcripts, 88,693 non-redundant isoforms were identified with an average length of 2,497 bp and an N50 value of 2,726 bp, which was much longer than the formal grasshopper transcriptome assemblies. A total of 48,502 protein coding sequences were determined, and 37,569 were annotated in public gene function databases. A total of 36,488 simple tandem repeats, 12,765 long non-coding RNAs, and 414 transcription factors were also identified. According to gene functions, 70 heat shock proteins and 61 P450 genes that may correspond to drought adaptation of S. tsinlingensis were identified. The genome of Sphingonotus tsinlingensis is an ultra-large and complex genome. Full-length transcriptome sequencing is an ideal strategy for genomic research. This is the first full-length transcriptome of the genus Sphingonotus. The assembly parameters were better than all known grasshopper transcriptomes. This full-length transcriptome may be used to understand its genetic background and the evolution and ecology of grasshoppers.

genetics↗

bioRxiv2021

Generation and mutational analysis of a transgenic mouse model of human SRY

SRY is the Y-chromosomal gene that determines male sex development in humans and most other mammals. After three decades of study, we still lack a detailed understanding of which domains of the SRY protein are required to engage pathway of gene activity leading to testis development. Some insight has been gained from the study of genetic variations underlying differences/disorders of sex determination (DSD), but the lack of a system of experimentally generating SRY mutations and studying their consequences in vivo has limited progress in the field. To address this issue, we generated a mouse model carrying a human SRY transgene able to drive male sex determination in XX mice. Using CRISPR-Cas9 gene editing, we generated novel genetic modifications in each of SRYs three domains (N-terminal, HMG box, and C-terminal) and performed detailed analysis of their molecular and cellular effects on embryonic testis development. Our results provide new functional insights unique to human SRY and the causes of DSD, and present a versatile and powerful system in which to demonstrate causality of SRY variations in DSD, to functionally study the SRY variation database, and to characterize new pathogenic SRY variations found in DSD.

developmental biology↗

bioRxiv2021

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

Model systems that recapitulate the complexity of human tumors and the reality of variable treatment responses are urgently needed to better understand cancer biology and to develop more effective cancer therapies. Here we report development and characterization of a large bank of patient-derived xenografts (PDX) and matched organoid cultures from tumors that represent some of the greatest unmet needs in breast cancer research and treatment. These include endocrine-resistant, treatment-refractory, and metastatic breast cancers and, in some cases, multiple tumor collections from the same patients. The models can be grown long-term with high fidelity to the original tumors. We show that development of matched PDX and PDX-derived organoid (PDxO) models facilitates high-throughput drug screening that is feasible and cost-effective, while also allowing in vivo validation of results. Our data reveal consistency between drug screening results in organoids and drug responses in breast cancer PDX. Moreover, we demonstrate the feasibility of using these patient-derived models for precision oncology in real time with patient care, using a case of a triple negative breast cancer with early metastatic recurrence as an example. Our results uncovered an FDA-approved drug with high efficacy against the models. Treatment with the PDxO-directed therapy resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies. This work provides valuable new methods and resources for functional precision medicine and drug development for human breast cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/433268v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@134d5cdorg.highwire.dtl.DTLVardef@1c0a419org.highwire.dtl.DTLVardef@556a4forg.highwire.dtl.DTLVardef@1b68c9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗