Xiling Shen

Overview:

Dr. Shen’s research interests lie at precision medicine and systems biology. His lab integrates engineering, computational and biological techniques to study cancer, stem cells, microbiota and the nervous system in the gut. This multidisciplinary work has been instrumental in initiating several translational clinical trials in precision therapy. He is the director of the Woo Center for Big Data and Precision Health (DAP) and a core member of the Center for Genomics and Computational Biology (GCB).

Positions:

Hawkins Family Associate Professor

Biomedical Engineering
Pratt School of Engineering

Associate Professor in the Department of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Associate Professor in the Department of Electrical and Computer Engineering

Electrical and Computer Engineering
Pratt School of Engineering

Associate Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Associate Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

B.Sc. 2001

Stanford University

M.Sc. 2001

Stanford University

Ph.D. 2008

Stanford University

Grants:

Mapping Epigenetic Memory of Exposure New To Observe (MEMENTO)

Administered By
Biomedical Engineering
Awarded By
Defense Advanced Research Projects Agency
Role
Co Investigator
Start Date
End Date

A comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in pediatric obesity and obesity-targeted therapeutics

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Epigenomic Reprogramming in Patient Derived Models of Colorectal Cancer

Administered By
Biomedical Engineering
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

EFRI CEE : Engineering Technologies to Determine Causal Relationships Between Chromatin Structure and Gene Regulation

Administered By
Biomedical Engineering
Awarded By
National Science Foundation
Role
Principal Investigator
Start Date
End Date

An organotypic model recapitulating colon cancer microenvironment and metastasis

Administered By
Biomedical Engineering
Role
Principal Investigator
Start Date
End Date

Publications:

Mapping the peripheral nervous system in the whole mouse via compressed sensing tractography.

Objective.The peripheral nervous system (PNS) connects the central nervous system with the rest of the body to regulate many physiological functions and is therapeutically targeted to treat diseases such as epilepsy, depression, intestinal dysmotility, chronic pain, and more. However, we still lack understanding of PNS innervation in most organs because the large span, diffuse nature, and small terminal nerve bundle fibers have precluded whole-organism, high resolution mapping of the PNS. We sought to produce a comprehensive peripheral nerve atlas for use in future interrogation of neural circuitry and selection of targets for neuromodulation.Approach.We used diffusion tensor magnetic resonance imaging (DT-MRI) with high-speed compressed sensing to generate a tractogram of the whole mouse PNS. The tractography generated from the DT-MRI data is validated using lightsheet microscopy on optically cleared, antibody stained tissue.Main results.Herein we demonstrate the first comprehensive PNS tractography in a whole mouse. Using this technique, we scanned the whole mouse in 28 h and mapped PNS innervation and fiber network in multiple organs including heart, lung, liver, kidneys, stomach, intestines, and bladder at 70µm resolution. This whole-body PNS tractography map has provided unparalleled information; for example, it delineates the innervation along the gastrointestinal tract by multiple sacral levels and by the vagal nerves. The map enabled a quantitative tractogram that revealed relative innervation of the major organs by each vertebral foramen as well as the vagus nerve.Significance.This novel high-resolution nerve atlas provides a potential roadmap for future neuromodulation therapies and other investigations into the neural circuits which drive homeostasis and disease throughout the body.
Authors
Garrett, A; Rakhilin, N; Wang, N; McKey, J; Cofer, G; Anderson, RB; Capel, B; Johnson, GA; Shen, X
MLA Citation
Garrett, Aliesha, et al. “Mapping the peripheral nervous system in the whole mouse via compressed sensing tractography.J Neural Eng, vol. 18, no. 4, June 2021. Pubmed, doi:10.1088/1741-2552/ac0089.
URI
https://scholars.duke.edu/individual/pub1481735
PMID
33979784
Source
pubmed
Published In
J Neural Eng
Volume
18
Published Date
DOI
10.1088/1741-2552/ac0089

Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19.

Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.
Authors
Yu, C; Littleton, S; Giroux, NS; Mathew, R; Ding, S; Kalnitsky, J; Yang, Y; Petzold, E; Chung, HA; Rivera, GO; Rotstein, T; Xi, R; Ko, ER; Tsalik, EL; Sempowski, GD; Denny, TN; Burke, TW; McClain, MT; Woods, CW; Shen, X; Saban, DR
MLA Citation
Yu, Chen, et al. “Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19.Med (N Y), Apr. 2021. Pubmed, doi:10.1016/j.medj.2021.04.008.
URI
https://scholars.duke.edu/individual/pub1480358
PMID
33870241
Source
pubmed
Published In
Med (N Y)
Published Date
DOI
10.1016/j.medj.2021.04.008

The cancer microbiome atlas: a pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants.

Studying the microbial composition of internal organs and their associations with disease remains challenging due to the difficulty of acquiring clinical biopsies. We designed a statistical model to analyze the prevalence of species across sample types from The Cancer Genome Atlas (TCGA), revealing that species equiprevalent across sample types are predominantly contaminants, bearing unique signatures from each TCGA-designated sequencing center. Removing such species mitigated batch effects and isolated the tissue-resident microbiome, which was validated by original matched TCGA samples. Gene copies and nucleotide variants can further distinguish mixed-evidence species. We, thus, present The Cancer Microbiome Atlas (TCMA), a collection of curated, decontaminated microbial compositions of oropharyngeal, esophageal, gastrointestinal, and colorectal tissues. This led to the discovery of prognostic species and blood signatures of mucosal barrier injuries and enabled systematic matched microbe-host multi-omic analyses, which will help guide future studies of the microbiome's role in human health and disease.
Authors
Dohlman, AB; Arguijo Mendoza, D; Ding, S; Gao, M; Dressman, H; Iliev, ID; Lipkin, SM; Shen, X
MLA Citation
Dohlman, Anders B., et al. “The cancer microbiome atlas: a pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants.Cell Host Microbe, vol. 29, no. 2, Feb. 2021, pp. 281-298.e5. Pubmed, doi:10.1016/j.chom.2020.12.001.
URI
https://scholars.duke.edu/individual/pub1471127
PMID
33382980
Source
pubmed
Published In
Cell Host Microbe
Volume
29
Published Date
Start Page
281
End Page
298.e5
DOI
10.1016/j.chom.2020.12.001

Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity.

The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient.
Authors
Sarvestani, SK; Signs, S; Hu, B; Yeu, Y; Feng, H; Ni, Y; Hill, DR; Fisher, RC; Ferrandon, S; DeHaan, RK; Stiene, J; Cruise, M; Hwang, TH; Shen, X; Spence, JR; Huang, EH
MLA Citation
Sarvestani, Samaneh K., et al. “Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity.Nature Communications, vol. 12, no. 1, Jan. 2021, p. 262. Epmc, doi:10.1038/s41467-020-20351-5.
URI
https://scholars.duke.edu/individual/pub1471128
PMID
33431859
Source
epmc
Published In
Nature Communications
Volume
12
Published Date
Start Page
262
DOI
10.1038/s41467-020-20351-5

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.

While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb); http://cpag.oit.duke.edu ) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs with severe COVID-19 demonstrated colocalization of the GWAS signal of the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN), pointing to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches.
Authors
Wang, L; Balmat, TJ; Antonia, AL; Constantine, FJ; Henao, R; Burke, TW; Ingham, A; McClain, MT; Tsalik, EL; Ko, ER; Ginsburg, GS; DeLong, MR; Shen, X; Woods, CW; Hauser, ER; Ko, DC
MLA Citation
URI
https://scholars.duke.edu/individual/pub1469860
PMID
33398303
Source
pubmed
Published In
Medrxiv
Published Date
DOI
10.1101/2020.12.20.20248572