Joshua Snyder

Overview:

My research objective is to translate basic science discoveries into treatments and cures for cancer. My work primarily focuses on G protein-coupled receptors (GPCR)s as a primary target in cancer. GPCRs are the largest family of receptors encoded by the genome, tightly control cell signaling, and regulate physiology in a diversity of tissues. As such, they are historically among the best targets for small molecule therapy in the clinic. The leucine-rich G protein-coupled receptor-5 (Lgr5) is particularly interesting since it is expressed in stem and cancer stem cells in a myriad of tissues. However, the function of Lgr5 is still largely unknown. Currently, my work utilizes cutting-edge multidisciplinary approaches to tackle this important challenge. This includes genetic engineering of fluorescently labelled mice, high-content confocal microscopy and cell behavior modeling, organoid culturing and genome editing, and fluorescent based approaches for high-throughput screening of receptor trafficking.

 

Using these approaches, we have made several important discoveries regarding Lgr5 that are facilitating future studies. We found that Lgr5 drives the formation of very long cellular protrusions that serve as scaffolds for cell signaling. We are continuing to investigate the mechanistic importance of this finding using mouse models and intestinal organoid cultures to view this process in living mice. Another key observation was our discovery that Lgr5 internalization and trafficking are critical for regulating its function. Current work is now working toward a more mechanistic characterization of Lgr5 trafficking using fluorescent sensors that are capable of quantitatively assessing this dynamic process. We are also actively screening small molecule libraries in an effort to discover potential agonists/antagonists of Lgr5 that may be useful clinically in cancer treatment or in tissue regeneration. Lastly, we are continuing to develop additional technologies for directing gene expression in vivo in order to study the structure/function of tumor driver genes with greater sensitivity and more cellular resolution. Our strategy enables the simultaneous expression of multiple driver genes in vivo along with the ability to monitor their effects on cell fate and behavior. Importantly, many of the tools that we have developed are broadly applicable to other receptors and candidate tumor driver genes for which we are open for collaboration.

We are currently accepting applications for a post doctoral research fellow that will work on projects related to Lgr5 drug discovery and the cell fitness mechanisms driving tumorigenesis. Qualified applicants can apply here: https://careers.nationalpostdoc.org/job/postdoctoral-fellow-cell-biology-and-pharmacologycancer-biology/40147366/.

 

Positions:

Assistant Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2009

University of Pittsburgh School of Medicine

Grants:

Establishing the molecular and cellular mechanisms of Lgr5 signaling for controlling cancer stem cell behavior

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

A Cancer Rainbow Mouse for Simultaneous Assessment of Multiple Oncogenes

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Assistant Research Professor
Start Date
End Date

Beta-catenin modulates dopamine dependent signal transduction and behavior.

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
PI-Fellow
Start Date
End Date

Only the strong survive: Microenvironmental and genetic determinants of organotropism

Administered By
Surgery, Surgical Sciences
Role
Principal Investigator
Start Date
End Date

Establishing the molecular and cellular mechanisms of Lgr5 signaling for controlling cancer stem cell behavior

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion.

Field cancerization is a premalignant process marked by clones of oncogenic mutations spreading through the epithelium. The timescales of intestinal field cancerization can be variable and the mechanisms driving the rapid spread of oncogenic clones are unknown. Here we use a Cancer rainbow (Crainbow) modelling system for fluorescently barcoding somatic mutations and directly visualizing the clonal expansion and spread of oncogenes. Crainbow shows that mutations of ß-catenin (Ctnnb1) within the intestinal stem cell results in widespread expansion of oncogenes during perinatal development but not in adults. In contrast, mutations that extrinsically disrupt the stem cell microenvironment can spread in adult intestine without delay. We observe the rapid spread of premalignant clones in Crainbow mice expressing oncogenic Rspondin-3 (RSPO3), which occurs by increasing crypt fission and inhibiting crypt fixation. Crainbow modelling provides insight into how somatic mutations rapidly spread and a plausible mechanism for predetermining the intratumor heterogeneity found in colon cancers.
Authors
Boone, PG; Rochelle, LK; Ginzel, JD; Lubkov, V; Roberts, WL; Nicholls, PJ; Bock, C; Flowers, ML; von Furstenberg, RJ; Stripp, BR; Agarwal, P; Borowsky, AD; Cardiff, RD; Barak, LS; Caron, MG; Lyerly, HK; Snyder, JC
MLA Citation
Boone, Peter G., et al. “A cancer rainbow mouse for visualizing the functional genomics of oncogenic clonal expansion..” Nat Commun, vol. 10, no. 1, Dec. 2019. Pubmed, doi:10.1038/s41467-019-13330-y.
URI
https://scholars.duke.edu/individual/pub1423128
PMID
31792216
Source
pubmed
Published In
Nature Communications
Volume
10
Published Date
Start Page
5490
DOI
10.1038/s41467-019-13330-y

Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients

Authors
Crosby, EJ; Gwin, WR; Chang, S; Maecker, HT; Lubkov, V; Snyder, JC; Broadwater, G; Hyslop, T; Osada, T; Hobeika, AC; Hartman, ZC; Morse, MA; Lyerly, HK
MLA Citation
Crosby, E. J., et al. “Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients.” Poster Session Abstracts, American Association for Cancer Research, 2019. Crossref, doi:10.1158/1538-7445.sabcs18-p2-09-16.
URI
https://scholars.duke.edu/individual/pub1404161
Source
crossref
Published In
Poster Session Abstracts
Published Date
DOI
10.1158/1538-7445.sabcs18-p2-09-16

hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia.

We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein-coupled receptor, Calcitonin Receptor-Like Receptor (hCALCRL). Homozygosity results in fetal demise from hydrops fetalis, while heterozygosity in females is associated with spontaneous miscarriage and subfertility. Using molecular dynamic modeling and in vitro biochemical assays, we show that the hCLR(V205del) mutant results in misfolding of the first extracellular loop, reducing association with its requisite receptor chaperone, receptor activity modifying protein (RAMP), translocation to the plasma membrane and signaling. Using three independent genetic mouse models we establish that the adrenomedullin-CLR-RAMP2 axis is both necessary and sufficient for driving lymphatic vascular proliferation. Genetic ablation of either lymphatic endothelial Calcrl or nonendothelial Ramp2 leads to severe NIHF with embryonic demise and placental pathologies, similar to that observed in humans. Our results highlight a novel candidate gene for human congenital NIHF and provide structure-function insights of this signaling axis for human physiology.
Authors
Mackie, DI; Al Mutairi, F; Davis, RB; Kechele, DO; Nielsen, NR; Snyder, JC; Caron, MG; Kliman, HJ; Berg, JS; Simms, J; Poyner, DR; Caron, KM
MLA Citation
Mackie, Duncan I., et al. “hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia..” J Exp Med, vol. 215, no. 9, Sept. 2018, pp. 2339–53. Pubmed, doi:10.1084/jem.20180528.
URI
https://scholars.duke.edu/individual/pub1344278
PMID
30115739
Source
pubmed
Published In
J Exp Med
Volume
215
Published Date
Start Page
2339
End Page
2353
DOI
10.1084/jem.20180528

Relevance of GPCR functional selectivity/biased signaling to drugs of abuse

Authors
Caron, M; Urs, N; Peterson, S; Daigle, T; Snyder, J
MLA Citation
Caron, Marc, et al. “Relevance of GPCR functional selectivity/biased signaling to drugs of abuse.” Faseb Journal, vol. 28, no. 1, FEDERATION AMER SOC EXP BIOL, 2014.
URI
https://scholars.duke.edu/individual/pub1301629
Source
wos
Published In
Faseb Journal
Volume
28
Published Date

β-Catenin-SOX2 signaling regulates the fate of developing airway epithelium.

Wnt-β-catenin signaling regulates cell fate during organ development and postnatal tissue maintenance, but its contribution to specification of distinct lung epithelial lineages is still unclear. To address this question, we used a Cre recombinase (Cre)-LoxP approach to activate canonical Wnt signaling ectopically in developing lung endoderm. We found that persistent activation of canonical Wnt signaling within distal lung endoderm was permissive for normal development of alveolar epithelium, yet led to the loss of developing bronchiolar epithelium and ectasis of distal conducting airways. Activation of canonical Wnt led to ectopic expression of a lymphoid-enhancing factor and a T-cell factor (LEF and TCF, respectively) and absence of SRY (sex-determining region Y)-box 2 (SOX2) and tumor protein p63 (p63) expression in proximal derivatives. Conditional loss of SOX2 in airways phenocopied epithelial differentiation defects observed with ectopic activation of canonical Wnt. Our data suggest that Wnt negatively regulates a SOX2-dependent signaling program required for developmental progression of the bronchiolar lineage.
Authors
Hashimoto, S; Chen, H; Que, J; Brockway, BL; Drake, JA; Snyder, JC; Randell, SH; Stripp, BR
MLA Citation
Hashimoto, Shuichi, et al. “β-Catenin-SOX2 signaling regulates the fate of developing airway epithelium..” J Cell Sci, vol. 125, no. Pt 4, Feb. 2012, pp. 932–42. Pubmed, doi:10.1242/jcs.092734.
URI
https://scholars.duke.edu/individual/pub800813
PMID
22421361
Source
pubmed
Published In
J Cell Sci
Volume
125
Published Date
Start Page
932
End Page
942
DOI
10.1242/jcs.092734