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:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Associate 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

Only the strong survive: Microenvironmental and genetic determinants of organotropism

Awarded By
Sage Bionetworks
Role
Principal Investigator
Start Date
End Date

Visualizing tumor heterogeneity in an immune intact and autochthonous mouse model of breast cancer

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

Mouse Paint: A massively combinatorial approach for illuminating tumor heterogeneity in True Color

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

Recording the natural history of cancer progression using a Crainbow model of HER2+ breast cancer

Administered By
Surgery, Surgical Sciences
Awarded By
Icahn School of Medicine at Mount Sinai
Role
Principal Investigator
Start Date
End Date

Publications:

Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity.

BACKGROUND: Despite multimodal adjuvant management with radiotherapy, chemotherapy and hormonal therapies, most surgically resected primary breast cancers relapse or metastasize. A potential solution to late and distant recurrence is to augment systemic antitumor immunity, in part by appropriately presenting tumor antigens, but also by modulating the immunosuppressive tumor microenvironment (TME). We previously validated this concept in models of murine carcinoma treated with a novel predominately microcavitating version of high-intensity focused ultrasound (HIFU), mechanical high-intensity focused ultrasound (M-HIFU). Here we elucidated the mechanisms of enhanced antitumor immunity by M-HIFU over conventional thermal high-intensity focused ultrasound (T-HIFU) and investigated the potential of the combinatorial strategy with an immune checkpoint inhibitor, anti-PD-L1 antibody. METHODS: The antitumor efficacy of treatments was investigated in syngeneic murine breast cancer models using triple-negative (E0771) or human ErbB-2 (HER2) expressing (MM3MG-HER2) tumors in C57BL/6 or BALB/c mice, respectively. Induction of systemic antitumor immunity by the treatments was tested using bilateral tumor implantation models. Flow cytometry, immunohistochemistry, and single-cell RNA sequencing were performed to elucidate detailed effects of HIFU treatments or combination treatment on TME, including the activation status of CD8 T cells and polarization of tumor-associated macrophages (TAMs). RESULTS: More potent systemic antitumor immunity and tumor growth suppression were induced by M-HIFU compared with T-HIFU. Molecular characterization of the TME after M-HIFU by single-cell RNA sequencing demonstrated repolarization of TAM to the immunostimulatory M1 subtype compared with TME post-T-HIFU. Concurrent anti-PD-L1 antibody administration or depletion of CD4+ T cells containing a population of regulatory T cells markedly increased T cell-mediated antitumor immunity and tumor growth suppression at distant, untreated tumor sites in M-HIFU treated mice compared with M-HIFU monotherapy. CD8 T and natural killer cells played major roles as effector cells in the combination treatment. CONCLUSIONS: Physical disruption of the TME by M-HIFU repolarizes TAM, enhances T-cell infiltration, and, when combined with anti-PD-L1 antibody, mediates superior systemic antitumor immune responses and distant tumor growth suppression. These findings suggest M-HIFU combined with anti-PD-L1 may be useful in reducing late recurrence or metastasis when applied to primary tumors.
Authors
Abe, S; Nagata, H; Crosby, EJ; Inoue, Y; Kaneko, K; Liu, C-X; Yang, X; Wang, T; Acharya, CR; Agarwal, P; Snyder, J; Gwin, W; Morse, MA; Zhong, P; Lyerly, HK; Osada, T
MLA Citation
Abe, Shinya, et al. “Combination of ultrasound-based mechanical disruption of tumor with immune checkpoint blockade modifies tumor microenvironment and augments systemic antitumor immunity.J Immunother Cancer, vol. 10, no. 1, Jan. 2022. Pubmed, doi:10.1136/jitc-2021-003717.
URI
https://scholars.duke.edu/individual/pub1506901
PMID
35039461
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
10
Published Date
DOI
10.1136/jitc-2021-003717

Dual Detection of Extracellular and Intracellular Domains of HER2/ERBB2 Reveals Distinct Patterns of Isoform Expression with Mechanistic and Therapeutic Implications

Authors
Hsieh, M; Mori, H; Rosa, J; Moon, H; Schuetter, L; Chen, Q; Snyder, J; Borowsky, A
MLA Citation
URI
https://scholars.duke.edu/individual/pub1480855
Source
wos-lite
Published In
Laboratory Investigation
Volume
101
Published Date
Start Page
113
End Page
114

HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.

A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing overtreatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near-infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes. In a phase I human study, systemically administered HS196 could be detected in malignant nodules within prostatectomy specimens. Single-cell RNA sequencing identified uptake of HS196 by malignant prostate epithelium from the peripheral zone (AMACR+ERG+EPCAM+ cells), including SYP+ neuroendocrine cells that are associated with therapeutic resistance and metastatic progression. A theranostic version of this molecule is under clinical testing.
Authors
Osada, T; Crosby, EJ; Kaneko, K; Snyder, JC; Ginzel, JD; Acharya, CR; Yang, X-Y; Polascik, TJ; Spasojevic, I; Nelson, RC; Hobeika, A; Hartman, ZC; Neckers, LM; Rogatko, A; Hughes, PF; Huang, J; Morse, MA; Haystead, T; Lyerly, HK
MLA Citation
Osada, Takuya, et al. “HSP90-Specific nIR Probe Identifies Aggressive Prostate Cancers: Translation from Preclinical Models to a Human Phase I Study.Mol Cancer Ther, vol. 21, no. 1, Jan. 2022, pp. 217–26. Pubmed, doi:10.1158/1535-7163.MCT-21-0334.
URI
https://scholars.duke.edu/individual/pub1499234
PMID
34675120
Source
pubmed
Published In
Mol Cancer Ther
Volume
21
Published Date
Start Page
217
End Page
226
DOI
10.1158/1535-7163.MCT-21-0334

HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.

HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the initial oncogenic event. Here a Cancer rainbow mouse simultaneously expressing fluorescently barcoded wildtype (WTHER2), exon-16 null (d16HER2), and N-terminally truncated (p95HER2) HER2 isoforms is used to trace tumorigenesis from initiation to invasion. Tumorigenesis was visualized using whole-gland fluorescent lineage tracing and single-cell molecular pathology. We demonstrate that within weeks of expression, morphologic aberrations were already present and unique to each HER2 isoform. Although WTHER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16HER2 and p95HER2 induced rapid tumor development. d16HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16HER2 and p95HER2 tumors as evidenced by oncogene-dependent changes in epithelial specification and the tumor microenvironment. These data provide direct experimental evidence that intratumor heterogeneity programs begin very early and well in advance of screen or clinically detectable breast cancer. IMPLICATIONS: Although all HER2 breast cancers are treated equally, we show a mechanism by which clinically undetected HER2 isoforms program heterogenous cancer phenotypes through biased epithelial specification and adaptations within the tumor microenvironment.
Authors
Ginzel, JD; Acharya, CR; Lubkov, V; Mori, H; Boone, PG; Rochelle, LK; Roberts, WL; Everitt, JI; Hartman, ZC; Crosby, EJ; Barak, LS; Caron, MG; Chen, JQ; Hubbard, NE; Cardiff, RD; Borowsky, AD; Lyerly, HK; Snyder, JC
MLA Citation
Ginzel, Joshua D., et al. “HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.Mol Cancer Res, vol. 19, no. 10, Oct. 2021, pp. 1699–711. Pubmed, doi:10.1158/1541-7786.MCR-21-0215.
URI
https://scholars.duke.edu/individual/pub1485787
PMID
34131071
Source
pubmed
Published In
Mol Cancer Res
Volume
19
Published Date
Start Page
1699
End Page
1711
DOI
10.1158/1541-7786.MCR-21-0215

Visualizing Cell Competition and Mechanisms of Occult Tumorigenesis Ex Vivo.

Authors
Ginzel, JD; Acharya, CR; Wang, P; Schmid, A; Boone, PG; Rochelle, LK; Roberts, W; Barak, LS; Caron, MG; Cardiff, RD; Borowsky, AD; Lyerly, HK; Snyder, JC
MLA Citation
Ginzel, Joshua D., et al. “Visualizing Cell Competition and Mechanisms of Occult Tumorigenesis Ex Vivo.In Vitro Cellular & Developmental Biology Animal, vol. 57, no. SUPPL 1, 2021, pp. S10–S10.
URI
https://scholars.duke.edu/individual/pub1484296
Source
wos-lite
Published In
In Vitro Cellular & Developmental Biology Animal
Volume
57
Published Date
Start Page
S10
End Page
S10