Biology subjects

wang, x.

Publications and source records attributed to wang, x..

At least 19 recordsLinked to original sources

bioRxiv2026

Kinematically-Dominated Regime Shapes Cell Traction Force Dynamics under Osmotic Shock

Adherent cells must continuously adapt to rapid environmental fluctuations to preserve mechanical integrity. However, conventional theoretical frameworks predominantly rely on quasi-static assumptions, thereby limiting their ability to capture the transient dynamics of cellular responses to high-rate perturbations, such as acute osmotic shocks. To address this limitation, we developed a biophysical model incorporating a Hill-type law that couples active cytoskeletal mechanics to cell-edge velocity, explaining the counterintuitive experimental observation that traction forces transiently decrease during rapid hypotonic swelling despite an increase in cell size. We further construct a kinematic-geometric phase diagram that connects classical quasi-static theories with our dynamic model. Moreover, we show that traction-force dynamics are sensitive to the loading rate and amplitude of osmotic shock. In addition, stiffness-associated simulations and supporting perturbation evidence suggest a cellular stiffness-associated recovery trend in which stiffer cells exhibit faster volume recovery driven by stronger recoil of hydrostatic pressure.

biophysics↗

bioRxiv2026

Cerebellar Normative Modeling Identifies Neuroanatomical Biotypes Predicting dTMS Response in Spinocerebellar Ataxia Type 3

BackgroundSpinocerebellar ataxia type 3 (SCA3) presents with significant clinical heterogeneity. Traditional case-control neuroimaging, based on group means, obscures inter-individual anatomical variability, hindering the identification of stratification biomarkers for interventions like Transcranial Magnetic Stimulation (TMS). MethodsTo quantify individual neuroanatomical deviations, we constructed a cerebellar normative model using a multi-center dataset of 2,071 healthy controls with 2,549 MRI scans. Gray matter volume deviations (Z-scores) were mapped across 27 cerebellar lobules in 114 genetically confirmed SCA3 patients, and unsupervised clustering was applied to identify neuroanatomical biotypes. Clinical relevance was assessed by associating biotypes with ataxia severity and deep TMS (dTMS) outcomes in a longitudinal subset . ResultsWe identified two distinct biotypes: Biotype 1 exhibited relative structural preservation (positive deviations) predominantly in the posterior cerebellum (lobules VIIB, VIIIA), whereas Biotype 2 was characterized by extensive atrophy (negative deviations) centered on the anterior motor cerebellum (lobules I-VI). Clinically, Biotype 2 patients presented with significantly more severe baseline ataxia. However, regarding treatment response, an inverse relationship was observed: Biotype 2 patients demonstrated significantly greater symptomatic improvement following dTMS compared to Biotype 1. To further identify the optimal neuromodulatory strategy for each biotype, we compared the therapeutic efficacy of repetitive TMS (rTMS) and dTMS. While both biotypes showed clinical improvement following rTMS, Biotype 1 exhibited a superior therapeutic response to rTMS relative to dTMS. Furthermore, feature weight analysis identified atrophy of the right lobule VIIB as a critical predictor of clinical severity in Biotype 2. ConclusionThis study demonstrates that normative modeling can decode SCA3 heterogeneity. The identification of these biotypes reveals a dissociation between baseline structural integrity and neuromodulatory responsiveness, suggesting that patients with severe anterior cerebellar atrophy may, counterintuitively, derive greater therapeutic benefit from dTMS. Furthermore, by comparing the therapeutic efficacy of rTMS and dTMS, we further clarified biotype-specific treatment responses. These findings support the use of individualized neuroanatomical mapping for patient stratification in precision medicine.

neuroscience↗

bioRxiv2026

A cis-regulatory variant in ASIP causes gray coat color in the donkey

BackgroundGray is one of the relatively rare coat colors in donkeys. The Hetian Gray donkey is a distinctive indigenous breed from the Xinjiang Uygur Autonomous Region of Northwestern China, characterized by progressive hair depigmentation with aging while retaining dark skin pigmentation. However, the genetic basis underlying this unique gray coat color phenotype remains unclear. ResultsTo elucidate the genetic basis, we conducted whole-genome resequencing of Gray and non-Gray donkeys. Genome-wide selection signature analyses identified a candidate region on chromosome 15. Subsequent fine-mapping using mass spectrometry-based genotyping of 42 loci refined the candidate interval and revealed a SNP within intron 2 of the ASIP gene, located in a genomic fragment with highly similar sequences, showing complete association with the gray coat color. Association analysis in an expanded population further confirmed a strong correlation between this variant and the gray phenotype. Gene expression analyses also supported the role of ASIP in regulating pigmentation in donkeys. ConclusionsThese findings identify a genetic determinant of gray coat color in donkeys and provide new insights into the molecular mechanisms underlying age-related depigmentation in domestic animals.

genomics↗

bioRxiv2026

Genomic Foundation Models Reveal Chromatin-Domain-Scale Transposable Element Impacts on Rice Genome Architecture

Alignment-based detection of transposable element (TE) insertion polymorphisms suffers from reference bias and multi-mapping errors in repetitive genomic regions, creating a fundamental validation bottleneck for population-scale structural variant catalogs. Here, we demonstrate that the OneGenome-Rice (OGR) genomic foundation model (GFM)--a 1.25 billion parameter Mixtral architecture trained on 422 rice genomes without TE annotations--provides an entirely orthogonal, alignment-free approach that resolves TE-mediated structural divergence at chromatin-domain resolution. At the CTB4a cold-tolerance locus on chromosome 4, OGR embeddings revealed that the aus subpopulation (NONA_BOKRA) carries 2.2-fold higher structural divergence from indica than japonica, consistent with its 728 subpopulation-exclusive cold-protective TE insertions. Sliding-window analysis across 4.4 megabases identified a 25.6-fold divergence enhancement at TE clusters relative to the conserved CTB4a gene body. Critically, the minimal effective resolution was established at approximately 20 kilobases--corresponding to the median size of topologically associating domains (TADs) in the rice genome--while individual TE sites at 500 base pairs were undetectable (P = 0.94). Non-neural baselines confirmed the signal derives from learned representations of genomic context rather than simple nucleotide statistics. These findings establish GFMs as orthogonal validation tools for population-scale TE genotyping and provide computational evidence that TE functional effects are organized at the chromatin-domain level, with direct implications for prioritizing functional TE variants in crop breeding.

plant biology↗

bioRxiv2025

IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by A Low-Affinity Antibody

Mechanistic studies of viral neutralization typically prioritize high-affinity antibodies, relegating low-affinity binders to the sidelines. We report P5-1C8, a Class 1 SARS-CoV-2 antibody that exemplifies this underexplored "low-affinity yet high-potency" phenotype, retaining strong neutralization of Omicron JN.1 despite markedly weakened trimer binding (KD = 225 nM; IC50 = 0.06 nM). Structural and biophysical analyses reveal that P5-1C8 engages WT and BA.1 spikes through canonical intra-spike bivalency, but with JN.1 it induces aggregation. Using virion-like nanoparticles displaying multiple spikes, we show that IgG remains bound with no detectable dissociation and triggers pronounced aggregation. Coarse-grained molecular dynamics delineate the stepwise pathway in which weak IgG-spike contacts seed aggregation via transient inter-spike bridging. Together, these findings establish the first mechanistic framework demonstrating how weak-binding antibodies can nonetheless achieve potent neutralization through higher-order aggregation, thereby expanding the conceptual landscape of antibody function and opening new directions for antibody evaluation and design. Graphical AbstractLow-affinity antibodies are frequently disregarded in discovery pipelines. This work reports P5-1C8, a Class 1 SARS-CoV-2 antibody with weak trimer binding (KD-to-IC50 > 3,700-fold) yet potent neutralization of Omicron JN.1. Structural, biophysical, functional and coarse-grained simulations collectively demonstrate that transient inter-spike IgG bridging seeds higher-order aggregation, which in turn drives neutralization and provides a mechanistic framework. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/691454v1_ufig1.gif" ALT="Figure 1000"> View larger version (79K): org.highwire.dtl.DTLVardef@1d4f132org.highwire.dtl.DTLVardef@1274400org.highwire.dtl.DTLVardef@e186a6org.highwire.dtl.DTLVardef@4f1870_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

CaMKII Phosphorylation of RyR2 is Essential for Arrhythmia in CPVT

BackgroundGain of function variants (GOF) in the intracellular calcium (Ca2+) release channel RYR2 predominately underlie the inherited arrhythmogenic syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Patients with CPVT are susceptible to life-threatening ventricular arrhythmias triggered by emotional or physical stress. Adrenergic stimulation activates calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates RYR2 on serine 2814 to enhance Ca2+ release. Here we assessed the in vivo requirement of this phosphorylation event to unmask the latent arrhythmic potential of CPVT-causing variants. MethodsUsing multiplex murine genomic engineering, we mutated the CaMKII phosphorylation site RYR2-S2814 site to alanine (S2814A) in conjunction with a novel CPVT GOF variant (RYR2-R4650I). We systematically interrogated the consequences of CaMKII phosphorylation site ablation on the same (cis) or opposite (trans) allele with the CPVT variant at multiple phenotypic levels. ResultsThe novel GOF variant Ryr2-R4650I conferred a risk of adrenergically inducible ventricular arrhythmia, including bi-directional ventricular tachycardia (BiVT). Ablation of the CaMKII RYR2-S2814 phosphorylation site on the same allele as the GOF variant completely abrogated inducible arrhythmia. In contrast, ablation of this site on the opposite allele did not significantly alter in frequency, type, or length of inducible ventricular tachycardia compared to animals heterozygous for the Ryr2-R4650I variant alone. Furthermore, allelic concordance of Ryr2-R4650I and Ryr2-S2814A did not inhibit adrenergically-induced enhancement of RYR2-dependent functions, including heart rate response, augmentation of cellular Ca2+ flux, or intracellular Ca2+ release. ConclusionsOur data strongly support the hypothesis that CaMKII phosphorylation of RYR2 at S2814 is necessary and sufficient to unmask the arrhythmogenic phenotype in CPVT. Furthermore, pro-arrhythmia caused by CaMKII-S2814 phosphorylation in CPVT is an intra-molecular event, with implications for therapeutic interventions.

physiology↗

bioRxiv2025

Telomere-to-telomere gap-free genome assembly of a male donkey and the identification of novel SVs associated with functional genes

Previous assemblies of the donkey genome remain with gaps and structural errors, and a complete donkey genome will greatly facilitate genetic research related to donkeys. In the present study, a 2.78-Gb telomere-to-telomere gap-free donkey genome (CAU_T2T_donkey) was assembled, including a 29.78-Mb Y chromosome, aided by ONT and trio-binning approach. CAU_T2T_donkey corrected the structural errors of previous assemblies and added a total of 153.8-Mb previously unresolved regions and 354 genes to the reference genome EquAss-T2T_v2. We identified a 1.9-Mb PAR on CAU_T2T_donkey-chromosome Y, and added 17.1Mb regions and 75 new genes to the chromosome Y of the previous reference genome ASM1607732v2. Multi-copy genes, such as TSPY, L1RE, ETY, HSFY, and ETSTY were also identified in CAU_T2T_donkey-chromosome Y. Totally 6 types of repetitive sequences in centromeric regions were identified, and the features of the centromeric regions were revealed, and satellite-free centromeres were identified. We aligned HiFi long-read sequences of donkeys from six breeds against CAU_T2T_donkey and identified SVs in previously unresolved regions, and some of the novel SVs were located in functional genes, such as AOX1 (Chr4:DEL61), ASIC2 (Chr13:INS954), and Twist2 (Chr19:DEL98).

genomics↗

bioRxiv2025

A Gm6AG-binding protein from Vibrio cholerae.

Most known modification-dependent restriction endonucleases target 5-methylcytosine, only a few N6-methyladenine (6mA)-dependent restriction endonucleases have been well-characterized, and the majority of them recognize the G6mATC motif (e.g., DpnI, HHPV4I). Here, we report the identification of a novel 6mA-dependent DNA-binding protein from Vibrio cholerae, VchI, which specifically recognizes the G6mAG motif. VchI contains a winged helix (wH) domain that is homologous to the wH domain in DpnI. However, several key residues involved in 6mA recognition differ between VchI and DpnI, which may contribute to the discrepancy in their recognition specificities. These findings advance our understanding of prokaryotic 6mA modification diversity and the 6mA recognition mechanism of the wH domain, while simultaneously providing an innovative tool for epigenetic research.

biochemistry↗

bioRxiv2025

Peritoneal cavity-derived GATA6+ macrophages inhibit fibrosis through IL33 in endometrium

Macrophages exhibit a high degree of plasticity and play pivotal roles both in the normal physiological cycle of the endometrium and in its regeneration following injury. Although some new subsets of endometrial macrophages have been identified, their origins and functions remain to be further explored. In this study, we employed single-cell sequencing to analyze the endometrium of patients with normal endometrium and intrauterine adhesion (IUA) caused by injury. We identified a unique subset of macrophages distinguished by the expression of GATA6, a marker indicative of cavity macrophages. We verified that these GATA6+ macrophages were large peritoneal macrophages (LPMs) that migrated from the peritoneal cavity to the injured endometrium. Upon activation by injured endometrium, these LPMs demonstrated increased expression of Interleukin-33 (IL33), mediated by the Lars-Fos signaling axis, which interacts with the IL33 enhancer. Moreover, our studies revealed that IL33 derived from LPMs inhibited the differentiation of endometrial stromal cells (ESCs) into myofibroblasts, a critical step in the development of endometrial fibrosis. Furthermore, we confirmed the inhibitory effect occurred through the binding of IL33 to the ST2 receptor on ESCs, leading to the upregulation of JMJD3 and subsequent suppression of myofibroblast differentiation. Our findings highlight the essential role of LPMs in promoting endometrial repair and inhibiting fibrosis in IUA. Significance StatementThis study reveals the presence of a unique population of macrophages within the endometrium, originating from large peritoneal macrophages (LPMs), that are pivotal in endometrial repair. This finding offers new insights into the plasticity of macrophages and their potential therapeutic applications in treating endometrial fibrotic disorders.

immunology↗

bioRxiv2024

AKR1C mediates the acquired resistance to T-Dxd in a HER-2 positive gastric cancer line

Trastuzumab deruxtecan (T-Dxd), an anti-HER2 antibody-drug conjugate, has significantly enhanced clinical outcomes for patients as a HER2-directed therapy compared to previous standards of care. However, acquired resistance is always a concern, necessitating further investigation into the underlying resistance mechanism. In this study, we successfully established T-Dxd-resistant cell line (N87-R) by exposing HER2-positive N87 gastric cancer cells to increasing concentrations of T-Dxd, and demonstrated its resistance phenotype both in vitro and in vivo. While there were no changes in HER2 expression or T-Dxd binding in N87-R, a signature of drug metabolism genes were found upregulated, among which AKR1C played a critical role in the resistance mechanism. The resistance phenotype of N87-R cells was mitigated by both siRNA-mediated knockdown of AKR1C and pharmacological inhibition of its enzymatic activity. Our preclinical study underscores the critical role of AKR1C function in mediating T-Dxd resistance and suggests potential therapeutic innovation for combating T-Dxd resistance.

cancer biology↗

bioRxiv2024

Distinct Binding Modes of Inter-Spike Cross-Linking Suggest a Supplementary Mechanism for SARS-CoV-2 Antibody Neutralization

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its Omicron subvariants drastically amplifies transmissibility, infectivity, and immune escape, mainly due to their resistance to most neutralizing antibodies. Thus, exploring the mechanisms underlying antibody evasion is crucial. Although the full-length native form of antibody, immunoglobulin G (IgG), offers valuable insights into the neutralization, structural investigations primarily focus on the fragment of antigen-binding (Fab). Here, we employ single-particle cryo-electron microscopy (cryo-EM) to characterize a W328-6H2 antibody, in its native IgG form complexed with severe acute respiratory syndrome (SARS), severe acute respiratory syndrome coronavirus 2 wild-type (WT) and Omicron variant BA.1 spike protein (S). Three high-resolution structures reveal that the full-length IgG forms a centered head-to-head dimer of trimer when bound fully stoichiometrically with both SARS and WT S, while adopting a distinct offset configuration with Omicron BA.1 S. Combined with functional assays, our results suggest that, beyond the binding affinity between the RBD epitope and Fab, the higher-order architectures of S trimer and full-length IgG play an additional role in neutralization, elucidate a potential molecular basis of Omicron immune escape, and expand our understanding on antibody evasion mechanisms.

immunology↗

bioRxiv2023

Increased multiplexity in optical tissue clearing-based 3D immunofluorescence microscopy of the tumor microenvironment by LED photobleaching

Optical tissue clearing and three-dimensional (3D) immunofluorescence (IF) microscopy have been transforming imaging of the complex tumor microenvironment (TME). However, current 3D IF microscopy has restricted multiplexity; only three or four cellular and non-cellular TME components can be localized in a cleared tumor tissue. Here we report a LED photobleaching method and its application for 3D multiplexed optical mapping of the TME. We built a high-power LED light irradiation device and temperature-controlled chamber for completely bleaching fluorescent signals throughout optically cleared tumor tissues without compromise of tissue and protein antigen integrity. With newly developed tissue mounting and selected region-tracking methods, we established a cyclic workflow involving IF staining, tissue clearing, 3D confocal microscopy, and LED photobleaching. By registering microscope channel images generated through three work cycles, we produced 8-plex image data from individual 400 m-thick tumor macrosections that visualize various vascular, immune, and cancer cells in the same TME at tissue-wide and cellular levels in 3D. Our method was also validated for quantitative 3D spatial analysis of cellular remodeling in the TME after immunotherapy. These results demonstrate that our LED photobleaching system and its workflow offer a novel approach to increase the multiplexing power of 3D IF microscopy for studying tumor heterogeneity and response to therapy.

cancer biology↗

bioRxiv2023

A glutamatergic DRN-VTA pathway for neuropathic pain and comorbid depression-like behavior modulation

Chronic pain causes both physical suffering and comorbid mental disorders such as depression. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here, we report a pathway from vesicular glutamate transporter3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN[->]DAVTA), of which population activity in response to innocuous mechanical stimuli and sucrose consumption, is respectively inhibited and attenuated by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN[->]DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN[->]DAVTA activation alleviates neuropathic pain and comorbid depression-like behavior (CDB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesia and antidepressant effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN[->]DAVTA inhibition produces pain-like hypersensitivity and depression-like behavior in healthy mice. These findings reveal a novel VGluT3DRN[->]DAVTA[->]D2/D1NAcMed pathway in establishing and modulating chronic pain and comorbid depressive-like behavior.

neuroscience↗

bioRxiv2022

IndepthPathway: an integrated tool for in-depth pathway enrichment analysis based on bulk and single cell sequencing data

Single-cell sequencing (SCS) enables exploring the pathways and processes of cells, and cell populations. However, there is a paucity of pathway enrichment methods designed to tolerate the high noise and low gene coverage of this technology. When gene expression data are noisy and signals are sparse, testing pathway enrichment based on the genes expression may not yield statistically significant results which is particularly problematic when detecting the pathways enriched in less abundant cells that are vulnerable to disturbances. In this project, we developed a Weighted Concept Signature Enrichment Analysis (WCSEA) algorithm specialized for pathway enrichment analysis from single cell transcriptomics (scRNA-seq). WCSEA took a broader approach for assessing the functional relations of pathway gene sets to differentially expressed genes, and leverage the cumulative signature of molecular concepts characteristic of the highly differentially expressed genes, which we termed as the universal concept signature, to tolerate the high noise and low coverage of this technology. We then incorporated WCSEA into a R package called "IndepthPathway" for biologists to broadly leverage this method for pathway analysis based on bulk and single cell sequencing data. Through simulating technical variability and dropouts in gene expression characteristic of scRNA-seq as well as benchmarking on a real dataset of matched single cell and bulk RNAseq data, we demonstrate that IndepthPathway presents outstanding stability and depth in pathway enrichment results under stochasticity of the data, thus will substantially improve the scientific rigor of the pathway analysis for single cell sequencing data. The IndepthPathway package is available through: https://github.com/wangxlab/IndepthPathway.

bioinformatics↗

bioRxiv2022

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a several spinal muscular atrophy mouse model

Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron (SMN) proteins, there is growing evidence that non-neuronal cells play important roles in SMA pathogenesis. However, transcriptome alterations occurring at the single-cell level in SMA spinal cord remain unknown, preventing us from fully comprehending the role of specific cells. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and identified ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice was significantly reduced. A dimensionality reduction analysis revealed 29 cell subtypes and their differentially expressed gene. A subpopulation of vascular fibroblasts showed the most significant change in the SMA spinal cord at the single-cell level. This subpopulation was drastically reduced, possibly causing vascular defects and resulting in widespread protein synthesis and energy metabolism reductions in SMA mice. This study reveals for the first time a single-cell atlas of the spinal cord of mice with severe SMA, and sheds new light on the pathogenesis of SMA.

neuroscience↗

bioRxiv2022

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 [A]. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

biophysics↗

bioRxiv2021

Nrf2 mediated ER-phagy protects against oxidative damage in intervertebral disc degeneration

Intervertebral disc degeneration (IDD) increases the risk of low back pain (LBP). Oxidative stress may induce cellular damage and contribute to various diseases including IDD. Endoplasmic reticulum autophagy (ER-phagy) is a specific type of autophagy, its role in oxidative stress induced damage as well as in IDD is unknown. This study explores the role of ER-phagy in oxidative damage in intervertebral disc nucleus pulposus cells (NPCs), as well as the Nrf2/FAM134B axis in ER-phagy regulation and IDD therapy. We found ER-phagy was decreased in NPCs during oxidative stress; while FAM134B may promote ER-phagy and alleviate oxidative stress induced ER-stress and apoptosis. In addition, the nuclear transcription factor Nrf2 may promote the expression of FAM134B as well as ER-phagy, and suppress ER-stress and apoptosis in NPCs. Furthermore, overexpression of FAM134B and Nrf2 could effectively attenuate the progression of IDD in rats in vivo. These results suggest Nrf2/FAM134B mediated ER-phagy may combat oxidative damage in cells; meanwhile, ER-phagy as well as Nrf2 could be potential therapeutic targets for IDD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/469451v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@188b390org.highwire.dtl.DTLVardef@1c4e4f6org.highwire.dtl.DTLVardef@193fe77org.highwire.dtl.DTLVardef@12770e2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

An integral genomic signature approach for tailored cancer targeted therapy using genome-wide sequencing data

With the advent of low-cost sequencing, transcriptome and genome sequencing is expected to become clinical routine and transform precision oncology within next decade. However, viable genome-wide modeling methods that can facilitate rational selection of patients for tailored intervention while tolerating sequencing biases are far lacking. Here we propose an integral genomic signature (iGenSig) analysis as a new class of transparent, interpretable, and resilient methods for precision oncology based on multiple types of genome-wide sequencing data. We postulate that the redundant high-dimensional genomic features, which are typically eliminated during multi-omics modeling, may help overcome the sequencing biases. We thus conceive a novel method that models the therapeutic response using the high-dimensional transcriptional and mutational features predictive of tumor response, which we termed as an integral genomic signature (iGenSig), and then algorithmically resolve the feature redundancy tailored for each patient subject. Using genomic dataset of chemical perturbations, we developed the iGenSig models for predicting targeted therapy responses, and applied selected models to independent datasets for cancer cell lines, patient-derived xenografts, and patient subjects. iGenSig models exhibit outstanding cross-dataset performance compared to artificial intelligence methods, with exceptional resilience against simulated errors in genomic features. In particular, the iGenSig model for the EGFR inhibitor Erlotinib significantly predicted the responses of patient-derived xenografts and patients from a clinical trial, biological interpretation of which led to new insights into the predictive signature pathways with clinical relevance. Together, iGenSig will provide a computational infrastructure to empower tailored cancer intervention based on genome-wide sequencing data.

bioinformatics↗