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Featured researches published by Bryan A. Smith.


Cancer Cell | 2016

N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

John K. Lee; John W. Phillips; Bryan A. Smith; Jung Wook Park; Tanya Stoyanova; Erin F. McCaffrey; Robert Baertsch; Artem Sokolov; Justin G. Meyerowitz; Colleen Mathis; Donghui Cheng; Joshua M. Stuart; Kevan M. Shokat; W. Clay Gustafson; Jiaoti Huang; Owen N. Witte

MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.


Proceedings of the National Academy of Sciences of the United States of America | 2015

A basal stem cell signature identifies aggressive prostate cancer phenotypes

Bryan A. Smith; Artem Sokolov; Vladislav Uzunangelov; Robert Baertsch; Yulia Newton; Kiley Graim; Colleen Mathis; Donghui Cheng; Joshua M. Stuart; Owen N. Witte

Significance Aggressive cancers often possess functional and molecular traits characteristic of normal stem cells. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. Here, we transcriptionally profiled epithelial populations from the human prostate and show that aggressive prostate cancer is enriched for a prostate basal stem cell signature. Within prostate cancer metastases, histological subtypes had varying enrichment of the stem cell signature, with small cell neuroendocrine carcinoma being the most stem cell-like. We further found that small cell neuroendocrine carcinoma and the prostate basal stem cell share a common transcriptional program. Targeting normal stem cell transcriptional programs may provide a new strategy for treating advanced prostate cancer. Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.


Cell | 2016

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer

Justin M. Drake; Evan O. Paull; Nicholas A. J. Graham; John K. Lee; Bryan A. Smith; Bjoern Titz; Tanya Stoyanova; Claire M. Faltermeier; Vladislav Uzunangelov; Daniel E. Carlin; Daniel Teo Fleming; Christopher K. Wong; Yulia Newton; Sud Sudha; Ajay A. Vashisht; Jiaoti Huang; James A. Wohlschlegel; Thomas G. Graeber; Owen N. Witte; Joshua M. Stuart

We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.


Proceedings of the National Academy of Sciences of the United States of America | 2016

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Tanya Stoyanova; Mireille Riedinger; Shu Lin; Claire M. Faltermeier; Bryan A. Smith; Kelvin X. Zhang; Catherine C. Going; Andrew S. Goldstein; John K. Lee; Justin M. Drake; Meghan A. Rice; En-Chi Hsu; Behdokht Nowroozizadeh; Brandon Castor; Sandra Y. Orellana; Steven M. Blum; Donghui Cheng; Kenneth J. Pienta; Robert E. Reiter; Sharon J. Pitteri; Jiaoti Huang; Owen N. Witte

Significance A high nuclear Notch homolog 1, translocation-associated (Notch1) intracellular domain level distinguishes high-risk prostate cancer and castration-resistant prostate cancer from benign and low/intermediate-risk prostate cancer. Chronic activation of Notch1 cooperates with multiple oncogenic pathways altered in early prostate cancer, including AKT, Myc, and Ras/Raf/MAPK, to promote progression to androgen ablation-resistant prostate adenocarcinoma. Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.


Proceedings of the National Academy of Sciences of the United States of America | 2016

Functional screen identifies kinases driving prostate cancer visceral and bone metastasis

Claire M. Faltermeier; Justin M. Drake; Peter M. Clark; Bryan A. Smith; Yang Zong; Carmen Volpe; Colleen Mathis; Colm Morrissey; Brandon Castor; Jiaoti Huang; Owen N. Witte

Significance Therapies are urgently needed to treat metastatic prostate cancer. Mutationally activated and wild-type kinases such as BCR-ABL and BTK are effective therapeutic targets in multiple cancers. Genetically altered kinases are rare in prostate cancer. Wild-type kinases may be implicated in prostate cancer progression, but their therapeutic potential in metastatic prostate cancer remains unknown. Using phosphoproteomics and gene expression datasets, we selected 125 wild-type kinases implicated in human prostate cancer metastasis to screen for metastatic ability in vivo. The RAF family, MERTK, and NTRK2 drove prostate cancer bone and visceral metastasis and were highly expressed in human metastatic prostate cancer tissues. These studies reveal that wild-type kinases can drive metastasis and that the RAF family, MERTK, and NTRK2 may represent important therapeutic targets. Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.


Proceedings of the National Academy of Sciences of the United States of America | 2018

Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer

John K. Lee; Nathanael J. Bangayan; Timothy Chai; Bryan A. Smith; Tiffany E. Pariva; Sangwon Yun; Ajay A. Vashisht; Qingfu Zhang; Jung Wook Park; Eva Corey; Jiaoti Huang; Thomas G. Graeber; James A. Wohlschlegel; Owen N. Witte

Significance Advanced prostate cancer is a deadly disease made up of multiple cancer subtypes that evolve during its natural history. Unfortunately, antibody- and cell-based therapies in development that target single tumor antigens found in conventional prostate cancer do not account for this heterogeneity. Here, we show that two major subtypes of advanced prostate cancer, prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC), exhibit distinct cell-surface expression profiles. Integrated analysis of gene expression and cell-surface protein expression of prostate cancer nominated multiple subtype-specific cell-surface antigens. We specifically characterize FXYD3 and CEACAM5 as targets for immune-based therapies in PrAd and NEPC and provide preliminary evidence of the antigen-specific cytotoxic activity of CEACAM5-directed chimeric antigen receptor T cells in NEPC. Prostate cancer is a heterogeneous disease composed of divergent molecular and histologic subtypes, including prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC). While PrAd is the major histology in prostate cancer, NEPC can evolve from PrAd as a mechanism of treatment resistance that involves a transition from an epithelial to a neurosecretory cancer phenotype. Cell surface markers are often associated with specific cell lineages and differentiation states in normal development and cancer. Here, we show that PrAd and NEPC can be broadly discriminated by cell-surface profiles based on the analysis of prostate cancer gene expression datasets. To overcome a dependence on predictions of human cell-surface genes and an assumed correlation between mRNA levels and protein expression, we integrated transcriptomic and cell-surface proteomic data generated from a panel of prostate cancer cell lines to nominate cell-surface markers associated with these cancer subtypes. FXYD3 and CEACAM5 were validated as cell-surface antigens enriched in PrAd and NEPC, respectively. Given the lack of effective treatments for NEPC, CEACAM5 appeared to be a promising target for cell-based immunotherapy. As a proof of concept, engineered chimeric antigen receptor T cells targeting CEACAM5 induced antigen-specific cytotoxicity in NEPC cell lines. Our findings demonstrate that the surfaceomes of PrAd and NEPC reflect unique cancer differentiation states and broadly represent vulnerabilities amenable to therapeutic targeting.


Science | 2018

Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage

Jung Wook Park; John K. Lee; Katherine M. Sheu; Liang Wang; Nikolas G. Balanis; Kim Nguyen; Bryan A. Smith; Chen Cheng; Brandon Tsai; Donghui Cheng; Jiaoti Huang; Siavash K. Kurdistani; Thomas G. Graeber; Owen N. Witte

Some (re)programming notes on cancer Epithelial cancers develop resistance to targeted therapies in a number of different ways. Several cancer types do so by undergoing phenotypic conversion to a highly aggressive cancer called small cell neuroendocrine carcinoma (SCNC). Whether distinct cancer types accomplish this “reprogramming” through the same mechanism has been unclear. Park et al. show that the same set of oncogenic factors transforms both normal lung and normal prostate epithelial cells into SCNCs that resemble clinical samples (see the Perspective by Kareta and Sage). This convergence of molecular pathways could potentially simplify the development of new therapies for SCNC, which is currently untreatable. Science, this issue p. 91; see also p. 30 Prostate and lung cancers convert to a drug-resistant, lethal form of cancer through the same reprogramming mechanism. The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.


Cancer Research | 2016

Abstract 3882: Patient-specific druggable networks in lethal prostate cancer through proteome-guided multi-omic integration

Justin M. Drake; Evan O. Paull; Nicholas A. J. Graham; John K. Lee; Bryan A. Smith; Tanya Stoyanova; Claire M. Faltermeier; Daniel E. Carlin; Ajay A. Vashisht; Jiaoti Huang; James A. Wohlschlegel; Thomas G. Graeber; Owen N. Witte; Joshua M. Stuart

Metastatic castration resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. The need to identify new actionable targets in this disease is crucial as we begin to examine the resistance mechanisms related to androgen withdrawal. Pathway activation of signaling proteins, such as kinases, are hypothesized to drive the progression of lethal CRPC. We set out to define the global picture of signaling pathways in lethal prostate cancer through dataset integration. We used clinical tissue from lethal metastatic CRPC patients obtained at rapid autopsy to evaluate and integrate previously published genomic and transcriptomic datasets combined with a new complete and extensive dataset of the phosphoproteome in metastatic CRPC for pathway analysis. This included extending our analysis of the phosphoproteome to phosphoserine and phosphothreonine peptides with our published phosphotyrosine peptide data. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues relative to treatment naive prostate cancer to synthesize a robust signaling network consisting of druggable kinase pathways for therapy. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Further, we were able to gather mRNA and phosphoproteome data from six individual patients where the integration of tissue samples from a single autopsy program allowed us to make inferences on the connections between the mRNA and phosphoproteome datasets. Individual patient profiles developed using these hallmarks revealed clinically relevant pathway information suitable for patient stratification and targeted therapies in lethal prostate cancer. Here we describe these pathways: personalized cancer hallmarks using an integrative phospho-signature (pCHIPs) that sheds light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients. Citation Format: Justin M. Drake, Evan O. Paull, Nicholas A. Graham, John K. Lee, Bryan A. Smith, Tanya Stoyanova, Claire M. Faltermeier, Daniel E. Carlin, Ajay Vashisht, Jiaoti Huang, James A. Wohlschlegel, Thomas G. Graeber, Owen N. Witte, Joshua M. Stuart. Patient-specific druggable networks in lethal prostate cancer through proteome-guided multi-omic integration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3882.


Molecular Cancer Research | 2015

Abstract A28: N-Myc drives small cell neuroendocrine cancer initiated from human prostate basal cells

John K. Lee; Bryan A. Smith; John W. Phillips; Jungwook Park; Tanya Stoyanova; Robert Baertsch; Artem Sokolov; Colleen Mathis; Donghui Cheng; Joshua M. Stuart; Jiaoti Huang; Owen N. Witte

Human small cell prostate carcinoma (SCPC) represents up to 25% of lethal castration-resistant prostate cancer. Molecular characterization of a panel of SCPCs recently identified frequent genomic amplification of both MYCN and AURKA. The oncogenic function of N-Myc has been characterized in many cancer types but its role in the initiation of human SCPC has not been defined. To investigate the function of N-Myc in human prostate transformation, we utilized a tissue regeneration model of human prostate cancer. Human prostate basal epithelial cells were isolated from benign primary prostate tissue from four independent human donors, infected with lentiviruses expressing the oncogenes N-Myc and activated (myristoylated) AKT1, mixed with mouse urogenital sinus mesenchyme, and grafted subcutaneously in immunodeficient NOD-SCID-IL2Rγnull mice. Palpable tumors were appreciated within 2-3 months and histological evaluation revealed regions of mixed high-grade adenocarcinoma and small cell carcinoma. The small cell carcinoma histology showed typical findings of high nuclear-to-cytoplasmic ratio, nuclear molding, stippled chromatin, and frequent mitotic and apoptotic features. Immunohistochemical analysis demonstrated low to absent androgen receptor (AR) staining in both the adenocarcinoma and small cell carcinoma. Further, we found heterogeneous staining for neuroendocrine markers including neural cell adhesion molecule 1, chromogranin A, synaptophysin, thyroid transcription factor 1, and forkhead box A2 in the regions of small cell carcinoma in support of the histological diagnosis. To assess the androgen dependence of tumor growth, regenerated N-Myc and activated AKT1 tumors derived from the lentiviral infection of primary human prostate basal cells were passaged in either intact or castrate immunodeficient mice. Tumors were propagated both in the presence and absence of androgens and showed a small but progressive enrichment of the small cell carcinoma over the adenocarcinoma with successive passage in castrate hosts. Molecular profiling by RNA-Seq of three regenerated N-Myc and activated AKT1 tumors showed a significant resemblance to a subset of human SCPC clinical specimens. Further, the adenocarcinoma and small cell carcinoma components of each tumor were remarkably similar at the transcriptional level despite their differences in histological appearance. In conclusion, we have established a novel model of human small cell prostate cancer arising from benign human prostate basal cells. Overexpression of N-Myc and activated AKT1 in basal cells produces tumors that recapitulate the histology, immunophenotype, and transcriptional profile of human SCPC. These findings support a direct role for N-Myc in the neuroendocrine transformation of basal cells in the human prostate. Further studies are ongoing to elucidate the mechanisms by which N-Myc induces a neuroendocrine differentiation program in prostate cancer. Citation Format: John K. Lee, Bryan A. Smith, John W. Phillips, Jungwook Park, Tanya I. Stoyanova, Robert Baertsch, Artem Sokolov, Colleen Mathis, Donghui Cheng, Joshua M. Stuart, Jiaoti Huang, Owen N. Witte. N-Myc drives small cell neuroendocrine cancer initiated from human prostate basal cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A28.


Cancer Research | 2015

Abstract 4985: Notch1 as a key mediator in promoting advanced castration-resistant prostate cancer

Tanya Stoyanova; Claire M. Faltermeier; Bryan A. Smith; Andrew S. Goldstein; Xi Zhang; Justin M. Drake; John G. Lee; Sandra Y. Orellana; Steven M. Blum; Donghui Cheng; Kenneth Pienta; Jiaoti Huang; Owen N. Witte

The first line of treatment for men with advanced prostate cancers is androgen deprivation therapy. However, the disease commonly relapses in its lethal metastatic form referred to as castration-resistant prostate cancer (CRPC). CRPC is the primary cause of prostate cancer specific mortality in men. Current therapies including chemotherapeutic agents improve median overall survival by only few months. The mechanisms that distinguish clinically localized indolent tumors from lethal CRPC are unclear. Here we demonstrate that ectopic expression of Notch1 promotes progression to poorly differentiated carcinoma when combined with pathways that are altered in advanced disease but are insufficient to drive aggressive prostate cancer alone. Notch1 driven tumors are resistant to androgen deprivation. Transcriptional profiling reveals that these tumors display features of epithelial to mesenchymal transition, a morphological change associated with tumor aggressiveness and metastasis. Our study provides the first functional evidence that Notch1 signaling axis is a key mediator in promoting advanced prostate cancer and may represent a new therapeutic target for the advanced disease. Note: This abstract was not presented at the meeting. Citation Format: Tanya Stoyanova, Claire Faltermeier, Bryan Smith, Andrew Goldstein, Xi Zhang, Justin Drake, John Lee, Sandra Orellana, Steven Blum, Donghui Cheng, Kenneth Pienta, Jiaoti Huang, Owen Witte. Notch1 as a key mediator in promoting advanced castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4985. doi:10.1158/1538-7445.AM2015-4985

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Owen N. Witte

University of California

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John K. Lee

University of Minnesota

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Donghui Cheng

University of California

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Colleen Mathis

University of California

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