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Somarelli, Jason Andrew

Positions:

Medical Instructor in the Department of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2009

Ph.D. — Florida International University

Grants:

Validation and interrogation of differentially expressed and alternatively spliced genes in African American prostate ca

Administered By
Duke Cancer Institute
AwardedBy
Department of Defense
Role
Postdoctoral Associate
Start Date
September 30, 2014
End Date
September 29, 2018

Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Administered By
Medicine, Medical Oncology
AwardedBy
Prostate Cancer Foundation
Role
Post Doctoral Trainee
Start Date
August 01, 2014
End Date
August 01, 2018

Testing the efficacy of AR degrading compounds in enzalutamide-resistant prostate cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Arvinas Inc.
Role
Principal Investigator
Start Date
January 05, 2017
End Date
January 04, 2018

Publications:

Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

Authors
Jolly, MK; Tripathi, SC; Somarelli, JA; Hanash, SM; Levine, H
MLA Citation
Jolly, MK, Tripathi, SC, Somarelli, JA, Hanash, SM, and Levine, H. "Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?." Molecular Oncology 11.7 (July 2017): 739-754.
Source
crossref
Published In
Molecular Oncology
Volume
11
Issue
7
Publish Date
2017
Start Page
739
End Page
754
DOI
10.1002/1878-0261.12084

EMT and MET: necessary or permissive for metastasis?

Authors
Jolly, MK; Ware, KE; Gilja, S; Somarelli, JA; Levine, H
MLA Citation
Jolly, MK, Ware, KE, Gilja, S, Somarelli, JA, and Levine, H. "EMT and MET: necessary or permissive for metastasis?." Molecular Oncology 11.7 (July 2017): 755-769.
Source
crossref
Published In
Molecular Oncology
Volume
11
Issue
7
Publish Date
2017
Start Page
755
End Page
769
DOI
10.1002/1878-0261.12083

Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells.

Phenotypic plasticity refers to a phenomenon in which cells transiently gain traits of another lineage. During carcinoma progression, phenotypic plasticity drives invasion, dissemination and metastasis. Indeed, while most of the studies of phenotypic plasticity have been in the context of epithelial-derived carcinomas, it turns out sarcomas, which are mesenchymal in origin, also exhibit phenotypic plasticity, with a subset of sarcomas undergoing a phenomenon that resembles a mesenchymal-epithelial transition (MET). Here, we developed a method comprising the miR-200 family and grainyhead-like 2 (GRHL2) to mimic this MET-like phenomenon observed in sarcoma patient samples.We sequentially express GRHL2 and the miR-200 family using cell transduction and transfection, respectively, to better understand the molecular underpinnings of these phenotypic transitions in sarcoma cells. Sarcoma cells expressing miR-200s and GRHL2 demonstrated enhanced epithelial characteristics in cell morphology and alteration of epithelial and mesenchymal biomarkers. Future studies using these methods can be used to better understand the phenotypic consequences of MET-like processes on sarcoma cells, such as migration, invasion, metastatic propensity, and therapy resistance.

Authors
Ware, KE; Gilja, S; Xu, S; Shetler, S; Jolly, MK; Wang, X; Bartholf Dewitt, S; Hish, AJ; Jordan, S; Eward, W; Levine, H; Armstrong, AJ; Somarelli, JA
MLA Citation
Ware, KE, Gilja, S, Xu, S, Shetler, S, Jolly, MK, Wang, X, Bartholf Dewitt, S, Hish, AJ, Jordan, S, Eward, W, Levine, H, Armstrong, AJ, and Somarelli, JA. "Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells." Journal of visualized experiments : JoVE 122 (April 7, 2017).
PMID
28448023
Source
epmc
Published In
Journal of Visualized Experiments
Issue
122
Publish Date
2017
DOI
10.3791/55520

PhyloOncology: Understanding cancer through phylogenetic analysis

Authors
Somarelli, JA; Ware, KE; Kostadinov, R; Robinson, JM; Amri, H; Abu-Asab, M; Fourie, N; Diogo, R; Swofford, D; Townsend, JP
MLA Citation
Somarelli, JA, Ware, KE, Kostadinov, R, Robinson, JM, Amri, H, Abu-Asab, M, Fourie, N, Diogo, R, Swofford, D, and Townsend, JP. "PhyloOncology: Understanding cancer through phylogenetic analysis." Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1867.2 (April 2017): 101-108.
Source
crossref
Published In
BBA - Reviews on Cancer
Volume
1867
Issue
2
Publish Date
2017
Start Page
101
End Page
108
DOI
10.1016/j.bbcan.2016.10.006

Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer.

Purpose: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach.Experimental Design: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential aCGH analyses of CTCs in the context of enzalutamide therapy.Results: All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3, while common genomic losses involved PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2 Analysis of aCGH in a sample with sequential enzalutamide-resistant visceral progression showed acquired loss of AR amplification concurrent with gain of MYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone.Conclusions: Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in AR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development. Clin Cancer Res; 23(5); 1346-57. ©2016 AACR.

Authors
Gupta, S; Li, J; Kemeny, G; Bitting, RL; Beaver, J; Somarelli, JA; Ware, KE; Gregory, S; Armstrong, AJ
MLA Citation
Gupta, S, Li, J, Kemeny, G, Bitting, RL, Beaver, J, Somarelli, JA, Ware, KE, Gregory, S, and Armstrong, AJ. "Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 23.5 (March 2017): 1346-1357.
PMID
27601596
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
23
Issue
5
Publish Date
2017
Start Page
1346
End Page
1357
DOI
10.1158/1078-0432.ccr-16-1211

Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2.

Phenotypic plasticity involves a process in which cells transiently acquire phenotypic traits of another lineage. Two commonly studied types of phenotypic plasticity are epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). In carcinomas, EMT drives invasion and metastatic dissemination, while MET is proposed to play a role in metastatic colonization. Phenotypic plasticity in sarcomas is not well studied; however, there is evidence that a subset of sarcomas undergo an MET-like phenomenon. While the exact mechanisms by which these transitions occur remain largely unknown, it is likely that some of the same master regulators that drive EMT and MET in carcinomas also act in sarcomas. In this study, we combined mathematical models with bench experiments to identify a core regulatory circuit that controls MET in sarcomas. This circuit comprises the microRNA 200 (miR-200) family, ZEB1, and GRHL2. Interestingly, combined expression of miR-200s and GRHL2 further upregulates epithelial genes to induce MET. This effect is phenocopied by downregulation of either ZEB1 or the ZEB1 cofactor, BRG1. In addition, an MET gene expression signature is prognostic for improved overall survival in sarcoma patients. Together, our results suggest that a miR-200, ZEB1, GRHL2 gene regulatory network may drive sarcoma cells to a more epithelial-like state and that this likely has prognostic relevance.

Authors
Somarelli, JA; Shetler, S; Jolly, MK; Wang, X; Bartholf Dewitt, S; Hish, AJ; Gilja, S; Eward, WC; Ware, KE; Levine, H; Armstrong, AJ; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Shetler, S, Jolly, MK, Wang, X, Bartholf Dewitt, S, Hish, AJ, Gilja, S, Eward, WC, Ware, KE, Levine, H, Armstrong, AJ, and Garcia-Blanco, MA. "Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2." Molecular and cellular biology 36.19 (October 2016): 2503-2513.
Website
http://hdl.handle.net/10161/13882
PMID
27402864
Source
epmc
Published In
Molecular and Cellular Biology
Volume
36
Issue
19
Publish Date
2016
Start Page
2503
End Page
2513
DOI
10.1128/mcb.00373-16

Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways.

The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET). Although there is substantial support for the role of EMT in driving cancer cell invasion and dissemination, much less is known about the importance of MET in the later steps of metastatic colonization. We created novel reporters, which integrate transcriptional and post-transcriptional regulation, to test whether MET is required for metastasis in multiple in vivo cancer models. In a model of carcinosarcoma, metastasis occurred via an MET-dependent pathway; however, in two prostate carcinoma models, metastatic colonization was MET independent. Our results provide evidence for both MET-dependent and MET-independent metastatic pathways.

Authors
Somarelli, JA; Schaeffer, D; Marengo, MS; Bepler, T; Rouse, D; Ware, KE; Hish, AJ; Zhao, Y; Buckley, AF; Epstein, JI; Armstrong, AJ; Virshup, DM; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Schaeffer, D, Marengo, MS, Bepler, T, Rouse, D, Ware, KE, Hish, AJ, Zhao, Y, Buckley, AF, Epstein, JI, Armstrong, AJ, Virshup, DM, and Garcia-Blanco, MA. "Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways." Oncogene 35.33 (August 2016): 4302-4311.
Website
http://hdl.handle.net/10161/11682
PMID
26751776
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
35
Issue
33
Publish Date
2016
Start Page
4302
End Page
4311
DOI
10.1038/onc.2015.497

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

Authors
Ware, KE; Somarelli, JA; Schaeffer, D; Li, J; Zhang, T; Park, S; Patierno, SR; Freedman, J; Foo, W-C; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Ware, KE, Somarelli, JA, Schaeffer, D, Li, J, Zhang, T, Park, S, Patierno, SR, Freedman, J, Foo, W-C, Garcia-Blanco, MA, and Armstrong, AJ. "Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer." Oncotarget 7.31 (August 2016): 50507-50521.
Website
http://hdl.handle.net/10161/15123
PMID
27409172
Source
epmc
Published In
Oncotarget
Volume
7
Issue
31
Publish Date
2016
Start Page
50507
End Page
50521
DOI
10.18632/oncotarget.10476

Carcinosarcomas: tumors in transition?

Carcinosarcomas are rare, biphasic tumors that are comprised of carcinomatous and sarcomatous elements. While the exact mechanism by which these two phenotypes arise within a single tumor remains unclear, molecular evidence indicates that the epitheliod and spindle-cell components share a clonal origin. We propose that the biphasic nature of these neoplasms may represent an extreme case of epithelial plasticity, in which an epithelial-like cell undergoes a transition to a more mesenchymal phenotype. The present review will discuss both the histological and molecular biological evidence of the involvement of epithelial plasticity in driving the mixed phenotypes observed in carcinosarcomas.

Authors
Somarelli, JA; Boss, M-K; Epstein, JI; Armstrong, AJ; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Boss, M-K, Epstein, JI, Armstrong, AJ, and Garcia-Blanco, MA. "Carcinosarcomas: tumors in transition?." Histology and histopathology 30.6 (June 2015): 673-687. (Review)
PMID
25587806
Source
epmc
Published In
Histology and Histopathology
Volume
30
Issue
6
Publish Date
2015
Start Page
673
End Page
687
DOI
10.14670/hh-30.673

Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition.

Metastatic dissemination requires carcinoma cells to detach from the primary tumor and invade through the basement membrane. To acquire these characteristics, epithelial tumor cells undergo epithelial-to-mesenchymal transitions (EMT), whereby cells lose polarity and E-cadherin-mediated cell-cell adhesion. Post-EMT cells have also been shown, or assumed, to be more migratory; however, there have been contradictory reports on an immortalized human mammary epithelial cell line (HMLE) that underwent EMT. In the context of carcinoma-associated EMT, it is not yet clear whether the change in migration and invasion must be positively correlated during EMT or whether enhanced migration is a necessary consequence of having undergone EMT. Here, we report that pre-EMT rat prostate cancer (PC) and HMLE cells are more migratory than their post-EMT counterparts. To determine a mechanism for increased epithelial cell migration, gene expression analysis was performed and revealed an increase in epidermal growth factor receptor (EGFR) expression in pre-EMT cells. Indeed, inhibition of EGFR in PC epithelial cells slowed migration. Importantly, while post-EMT PC and HMLE cell lines are less migratory, both remain invasive in vitro and, for PC cells, in vivo. Our study demonstrates that enhanced migration is not a phenotypic requirement of EMT, and migration and invasion can be uncoupled during carcinoma-associated EMT.

Authors
Schaeffer, D; Somarelli, JA; Hanna, G; Palmer, GM; Garcia-Blanco, MA
MLA Citation
Schaeffer, D, Somarelli, JA, Hanna, G, Palmer, GM, and Garcia-Blanco, MA. "Cellular migration and invasion uncoupled: increased migration is not an inexorable consequence of epithelial-to-mesenchymal transition." Molecular and cellular biology 34.18 (September 2014): 3486-3499.
PMID
25002532
Source
epmc
Published In
Molecular and Cellular Biology
Volume
34
Issue
18
Publish Date
2014
Start Page
3486
End Page
3499
DOI
10.1128/mcb.00694-14

U1 small nuclear RNA variants differentially form ribonucleoprotein particles in vitro

Authors
Somarelli, JA; Mesa, A; Rodriguez, CE; Sharma, S; Herrera, RJ
MLA Citation
Somarelli, JA, Mesa, A, Rodriguez, CE, Sharma, S, and Herrera, RJ. "U1 small nuclear RNA variants differentially form ribonucleoprotein particles in vitro." Gene 540.1 (April 2014): 11-15.
Source
crossref
Published In
Gene
Volume
540
Issue
1
Publish Date
2014
Start Page
11
End Page
15
DOI
10.1016/j.gene.2014.02.054

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance

Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches. © 2014 Springer Science+Business Media.

Authors
Bitting, RL; Schaeffer, D; Somarelli, JA; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Bitting, RL, Schaeffer, D, Somarelli, JA, Garcia-Blanco, MA, and Armstrong, AJ. "The role of epithelial plasticity in prostate cancer dissemination and treatment resistance." Cancer and Metastasis Reviews 33.2-3 (January 1, 2014): 441-468.
Source
scopus
Published In
Cancer and Metastasis Reviews
Volume
33
Issue
2-3
Publish Date
2014
Start Page
441
End Page
468
DOI
10.1007/s10555-013-9483-z

Fluorescence-based alternative splicing reporters for the study of epithelial plasticity in vivo.

Alternative splicing generates a vast diversity of protein isoforms from a limited number of protein-coding genes, with many of the isoforms possessing unique, and even contrasting, functions. Fluorescence-based splicing reporters have the potential to facilitate studies of alternative splicing at the single-cell level and can provide valuable information on phenotypic transitions in almost real time. Fibroblast growth factor receptor 2 (FGFR2) pre-mRNA is alternatively spliced to form the epithelial-specific and mesenchymal-specific IIIb and IIIc isoforms, respectively, which are useful markers of epithelial-mesenchymal transitions (EMT). We have used our knowledge of FGFR2 splicing regulation to develop a fluorescence-based reporter system to visualize exon IIIc regulation in vitro and in vivo. Here we show the application of this reporter system to the study of EMT in vitro in cell culture and in vivo in transgenic mice harboring these splicing constructs. In explant studies, the reporters revealed that FGFR2 isoform switching is not required for keratinocyte migration during cutaneous wound closure. Our results demonstrate the value of the splicing reporters as tools to study phenotypic transitions and cell fates at single cell resolution. Moreover, our data suggest that keratinocytes migrate efficiently in the absence of a complete EMT.

Authors
Somarelli, JA; Schaeffer, D; Bosma, R; Bonano, VI; Sohn, JW; Kemeny, G; Ettyreddy, A; Garcia-Blanco, MA
MLA Citation
Somarelli, JA, Schaeffer, D, Bosma, R, Bonano, VI, Sohn, JW, Kemeny, G, Ettyreddy, A, and Garcia-Blanco, MA. "Fluorescence-based alternative splicing reporters for the study of epithelial plasticity in vivo." RNA (New York, N.Y.) 19.1 (January 2013): 116-127.
PMID
23185039
Source
epmc
Published In
RNA (New York, N.Y.)
Volume
19
Issue
1
Publish Date
2013
Start Page
116
End Page
127
DOI
10.1261/rna.035097.112

Alternative splicing in multiple sclerosis and other autoimmune diseases.

Alternative splicing is a general mechanism for regulating gene expression that affects the RNA products of more than 90% of human genes. Not surprisingly, alternative splicing is observed among gene products of metazoan immune systems, which have evolved to efficiently recognize pathogens and discriminate between "self" and "non-self", and thus need to be both diverse and flexible. In this review we focus on the specific interface between alternative splicing and autoimmune diseases, which result from a malfunctioning of the immune system and are characterized by the inappropriate reaction to self-antigens. Despite the widespread recognition of alternative splicing as one of the major regulators of gene expression, the connections between alternative splicing and autoimmunity have not been apparent. We summarize recent findings connecting splicing and autoimmune disease, and attempt to find common patterns of splicing regulation that may advance our understanding of autoimmune diseases and open new avenues for therapy.

Authors
Evsyukova, I; Somarelli, JA; Gregory, SG; Garcia-Blanco, MA
MLA Citation
Evsyukova, I, Somarelli, JA, Gregory, SG, and Garcia-Blanco, MA. "Alternative splicing in multiple sclerosis and other autoimmune diseases." RNA Biol 7.4 (July 2010): 462-473. (Review)
Website
http://hdl.handle.net/10161/3963
PMID
20639696
Source
pubmed
Published In
RNA biology
Volume
7
Issue
4
Publish Date
2010
Start Page
462
End Page
473
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