Joshua Snyder

Overview:

I am the PI of the Cancer Initiation and Cancer Cell Behavior lab. Our research objective is to determine how cancer cells adapt and grow before cancer is diagnosed. Our lab is also part of the Center for Applied therapeutics where we share our models as tools for preclinical and translational research. To learn more about our research please visit the Cancer Initiation and Cancer Cell Behavior Lab's homepage.

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:

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins regardless of their canonical Gα protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.
Authors
Smith, JS; Pack, TF; Inoue, A; Lee, C; Zheng, K; Choi, I; Eiger, DS; Warman, A; Xiong, X; Ma, Z; Viswanathan, G; Levitan, IM; Rochelle, LK; Staus, DP; Snyder, JC; Kahsai, AW; Caron, MG; Rajagopal, S
MLA Citation
Smith, Jeffrey S., et al. “Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors.Science, vol. 371, no. 6534, Mar. 2021. Pubmed, doi:10.1126/science.aay1833.
URI
https://scholars.duke.edu/individual/pub1472830
PMID
33479120
Source
pubmed
Published In
Science
Volume
371
Published Date
DOI
10.1126/science.aay1833

Isoforms of GPCR proteins combine for diverse signalling.

Authors
Snyder, JC; Rajagopal, S
MLA Citation
Snyder, Joshua C., and Sudarshan Rajagopal. “Isoforms of GPCR proteins combine for diverse signalling.Nature, vol. 587, no. 7835, Nov. 2020, pp. 553–54. Pubmed, doi:10.1038/d41586-020-03001-0.
URI
https://scholars.duke.edu/individual/pub1467965
PMID
33149314
Source
pubmed
Published In
Nature
Volume
587
Published Date
Start Page
553
End Page
554
DOI
10.1038/d41586-020-03001-0

Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.

PURPOSE: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers. EXPERIMENTAL DESIGN: Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination. RESULTS: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2. CONCLUSIONS: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
Authors
Crosby, EJ; Acharya, CR; Haddad, A-F; Rabiola, CA; Lei, G; Wei, J-P; Yang, X-Y; Wang, T; Liu, C-X; Wagner, KU; Muller, WJ; Chodosh, LA; Broadwater, G; Hyslop, T; Shepherd, JH; Hollern, DP; He, X; Perou, CM; Chai, S; Ashby, BK; Vincent, BG; Snyder, JC; Force, J; Morse, MA; Lyerly, HK; Hartman, ZC
MLA Citation
Crosby, Erika J., et al. “Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.Clin Cancer Res, vol. 26, no. 17, Sept. 2020, pp. 4670–81. Pubmed, doi:10.1158/1078-0432.CCR-20-0389.
URI
https://scholars.duke.edu/individual/pub1453955
PMID
32732224
Source
pubmed
Published In
Clinical Cancer Research
Volume
26
Published Date
Start Page
4670
End Page
4681
DOI
10.1158/1078-0432.CCR-20-0389

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