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

Awarded By
Sage Bionetworks
Role
Principal Investigator
Start Date
End Date

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

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

Publications:

Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.
Authors
Kaneko, K; Osada, T; Morse, MA; Gwin, WR; Ginzel, JD; Snyder, JC; Yang, X-Y; Liu, C-X; Diniz, MA; Bodoor, K; Hughes, PF; Haystead, TA; Lyerly, HK
MLA Citation
Kaneko, Kensuke, et al. “Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.Commun Biol, vol. 3, no. 1, May 2020, p. 226. Pubmed, doi:10.1038/s42003-020-0956-7.
URI
https://scholars.duke.edu/individual/pub1441154
PMID
32385408
Source
pubmed
Published In
Communications Biology
Volume
3
Published Date
Start Page
226
DOI
10.1038/s42003-020-0956-7

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, p. 5490. 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

The complete mitochondrial genome sequence of the Canada goose (Branta canadensis).

The Canada goose (Branta canadensis) entire mitochondrial genome of a bird from Western Pennsylvania has 16,760 bp (GenBank accession number NC 007011) and has been analyzed for gene locations, length, start codon and stop codons. This genome from a bird harvested during the non-migratory season is the REFSEQ and the haplotype is designated GCC-A. There are two rRNAs, 22 tRNAs, 13 protein-coding regions, and 1 displacement loop region. The base composition of mtDNA was A (30.2%), G (15.1%), C (32.1%), and T (22.6%), so the percentage of A and T (52.8%) was slightly higher than G and C. All genes except ND6 and eight tRNA genes (Gln, Ala, Asn, Cys, Tyr, Ser, Pro and Glu) are encoded on the heavy strand. The gene arrangement is the same as most birds and differs from mammals by an inversion of the mtDNA at the connection between the D-loop and the ND5 junctions.
Authors
Snyder, JC; Mackaness, CA; Sopher, MR; Huber, JP; Disantis, EJ; Senecal, AJ; Vaughn, BP; Desantis, RS; Tobelmann, PE; Balauff, NMH; Barry, PM; Show, MD; Speering, LH; Genareo, CA; Brenner, FJ; Ray, DB
MLA Citation
Snyder, Joshua C., et al. “The complete mitochondrial genome sequence of the Canada goose (Branta canadensis).Mitochondrial Dna, vol. 26, no. 5, 2015, pp. 672–73. Pubmed, doi:10.3109/19401736.2013.840601.
URI
https://scholars.duke.edu/individual/pub1149064
PMID
24148019
Source
pubmed
Published In
Mitochondrial Dna
Volume
26
Published Date
Start Page
672
End Page
673
DOI
10.3109/19401736.2013.840601

Peg-L-Asparaginase (PL-A) in advanced multiple myeloma (MM): A novel agent with therapeutic potential.

Authors
Hussein, MA; Kurtzburg, J; Snyder, J; Kozak, C; McLain, DA; Bukowski, R
MLA Citation
Hussein, M. A., et al. “Peg-L-Asparaginase (PL-A) in advanced multiple myeloma (MM): A novel agent with therapeutic potential.Blood, vol. 88, no. 10, W B SAUNDERS CO, 1996, pp. 3607–3607.
URI
https://scholars.duke.edu/individual/pub1328230
Source
wos
Published In
Blood
Volume
88
Published Date
Start Page
3607
End Page
3607