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1. Investigation of the physiological response of radiation-induced cystitis patients using hyperbaric oxygen

Author

Farris Gulli, Timothy J. Geddes, Barbara L. Pruetz, and George D. Wilson

Subjects
Radiation cystitis, Prostate cancer, Hyperbaric oxygen, Biomarkers, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: In this pilot study we have taken a novel functional approach to assess whether differences exist in the activity of key genes involved in the response to radiation and oxidative stress between patients with radiation cystitis. Materials and methods: Arm 1 consisted of patients who had previously been treated for prostate cancer and who had received definitive radiation treatment and had subsequently developed cystitis and/or proctitis and were being treated by hyperbaric oxygen (HBO). Arm 2 consisted of patients who had never been treated by radiation but who were scheduled for HBO treatment for another pathology. The genes chosen for the study were HMOX1, NOS2, SOD2, TNFα, IL-6 and TGFβ. Blood and urine was collected pre and post HBO treatment. Results: Gene expression showed a significant difference in NOS2 (p = 0.0178) and TNFα (p = 0.037) between the control and cystitis patients. The plasma levels of VEGF-A were significantly elevated in cystitis patients and there was a strong trend for significant overexpression in urine. Comparing pre and post-dive samples showed little difference in both groups of patients except for VEGF-A which was reduced after the dive in plasma from cystitis patients. Conclusions: This study uncovered some physiological differences in patients with radiation-induced cystitis using HBO treatment as a stimulus to induce mild oxidative stress. Further research is ongoing to assess whether the acute exposure to HBO might be a physiological screening tool to identify patients susceptible to chronic radiation toxicity.

Published
2023
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2. Dacomitinib and gedatolisib in combination with fractionated radiation in head and neck cancer

Author

George D. Wilson, Thomas G. Wilson, Alaa Hanna, Mohamad Dabjan, Katie Buelow, John Torma, Brian Marples, and Sandra Galoforo

Subjects
Head and neck cancer, Radiation, Targeted agents, Xenografts, Growth delay, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background and purpose: There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective. Materials and methods: We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and in vivo. Results: Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway. Conclusions: Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC.

Published
2021
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3. Molecular Interaction Network Approach (MINA) identifies association of novel candidate disease genes

Author

Sam Kara, Alaa Hanna, Gerardo A. Pirela-Morillo, Conrad T. Gilliam, and George D. Wilson

Subjects
Science
Abstract

Molecular Interaction Network Approach (MINA) was used to elucidate candidate disease genes. The approach was implemented to identify novel gene association with commonly known autoimmune diseases [1]. In MINA, we evaluated the hypothesis that “network proximity” within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. There are now numerous examples of gene discoveries based upon network proximity between novel and previously identified disease genes (Yin et al., 2017 [2], Wang et al., 2011 [3], and Barrenas et al., 2009 [4]). This study extends the application of interaction networks to the interrogation of Genome Wide Association studies: first, by showing that a group of nine autoimmune diseases (AuD) genes “seed genes”, are connected in a highly non-random manner within a whole genome network; and second, by showing that the minimal number of connecting genes required to connect a maximal number of AuD candidate genes are highly enriched as candidate genes for AuD predisposing mutations. The findings imply that a threshold number of candidate genes for any heritable disorder can be used to “seed” a molecular interaction network that • Serves to validate the disease status of closely associated seed genes • Identifies genes that are highly enriched as novel candidate disease genes • Provides a strategy for elucidation of epistatic gene x gene interactionsThe method could provide a critical toll for understanding the genetic architecture of common traits and disorders. Method name: MINA, Molecular Interaction Network Approach, Keywords: Autoimmune diseases, Crohn’s disease (CD), Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), Psoriasis (PSO), Type-1 diabetes (T1D), Type-2 diabetes (T2D), Celiac disease (CeD), Multiple sclerosis (MS), Association, Molecular network

Published
2019
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4. Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer

Author

Kevin Blas, Thomas G. Wilson, Nathan Tonlaar, Sandra Galoforo, Alaa Hana, Brian Marples, and George D. Wilson

Subjects
Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background and purpose: In this study we have combined fractionated radiation treatment (RT) with two molecular targeted agents active against key deregulated signaling pathways in head and neck cancer. Materials and methods: We used two molecularly characterized, low passage HNSCC cell lines of differing biological characteristics to study the effects of binimetinib and buparlisib in combination with radiation in vitro and in vivo. Results: Buparlisib was active against both cell lines in vitro whereas binimetinib was more toxic to UT-SCC-14. Neither agent modified radiation sensitivity in vitro. Buparlisib significantly inhibited growth of UT-SSC-15 alone or in combination with RT but was ineffective in UT-SCC-14. Binimetinib did cause a significant delay with RT in UT-SCC-14 and it significantly reduced growth of the UT-SCC-15 tumors both alone and with RT. The tri-modality treatment was not as effective as RT with a single effective agent. Conclusions: No significant benefit was gained by the combined use of the two agents with RT even though each was efficacious when used alone. Keywords: Head and neck cancer, Radiation, Targeted agents, Xenografts, Growth delay

Published
2018
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5. Using global gene expression to discriminate thin melanomas with poor outcomes

Author

Zachary Hothem, Andrew Bayci, Bryan J. Thibodeau, Billie E. Ketelsen, Laura E. Fortier, Alison F. Uzieblo, Diane Cosner, Kristin Totoraitis, Richard D. Keidan, and George D. Wilson

Subjects
gene expression, melanoma, microarray, thin melanoma, surgical response, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Most melanomas present as thin lesions (≤1.0 mm) with a good prognosis; however, a small percentage of patients with thin lesions experience recurrence or metastasis. The aim of our study was to identify a distinct pattern of gene expression within thin melanomas known to have eventually metastasized to regional lymph nodes or distant sites compared with those that followed the typical course with good response to wide local excision alone. Patients who were disease-free for a minimum of 10 y served as controls (n = 10) to the experimental group who developed metastasis (n = 9). Laser capture microdissection was used to specifically isolate cancer cells from formalin-fixed paraffin-embedded tissue with subsequent gene expression analysis on Affymetrix Human Transcriptome Array 2.0 Arrays. Although gene expression differences were observed between the patients with thin melanoma with poor clinical outcome and those with good clinical outcome, neither the number of genes nor the magnitude of the fold difference was very substantial or significant. Cluster analysis with this subset of genes could definitively separate a subset of the poor responders from the good responders, but there remained a mixed group of tumors that could not be predicted from gene expression alone. Pathway analysis identified cellular processes that were regulated based on the response, including categories commonly associated with melanoma progression. Ultimately, we concluded that there were very few differences between these groups. Future research will be required and investigation of the mutational landscape may be another strategy to uncover genomic changes that drive recurrence and metastasis in thin melanoma.

Published
2017
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6. Cancer Stem Cell Signaling during Repopulation in Head and Neck Cancer

Author

George D. Wilson, Bryan J. Thibodeau, Laura E. Fortier, Barbara L. Pruetz, Sandra Galoforo, Brian Marples, Andrew M. Baschnagel, Jan Akervall, and Jiayi Huang

Subjects
Internal medicine, RC31-1245
Abstract

The aim of the study was to investigate cancer stem signaling during the repopulation response of a head and neck squamous cell cancer (HNSCC) xenograft after radiation treatment. Xenografts were generated from low passage HNSCC cells and were treated with either sham radiation or 15 Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21, after irradiation, 3 tumors per group were harvested for global gene expression, pathway analysis, and immunohistochemical evaluation. 316 genes were identified that were associated with a series of stem cell-related genes and were differentially expressed (p≤0.01 and 1.5-fold) at a minimum of one time point in UT-SCC-14 xenografts after radiation. The largest network of genes that showed significant changes after irradiation was associated with CD44, NOTCH1, and MET. c-MET and ALDH1A3 staining correlated with the changes in gene expression. A clear pattern emerged that was consistent with the growth inhibition data in that genes associated with stem cell pathways were most active at day 7 and day 12 after irradiation. The MET/CD44 axis seemed to be an important component of the repopulation response.

Published
2016
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7. The Importance of CD44 as a Stem Cell Biomarker and Therapeutic Target in Cancer

Author

Ranjeeta Thapa and George D. Wilson

Subjects
Internal medicine, RC31-1245
Abstract

CD44 is a cell surface HA-binding glycoprotein that is overexpressed to some extent by almost all tumors of epithelial origin and plays an important role in tumor initiation and metastasis. CD44 is a compelling marker for cancer stem cells of many solid malignancies. In addition, interaction of HA and CD44 promotes EGFR-mediated pathways, consequently leading to tumor cell growth, tumor cell migration, and chemotherapy resistance in solid cancers. Accumulating evidence indicates that major HA-CD44 signaling pathways involve a specific variant of CD44 isoforms; however, the particular variant almost certainly depends on the type of tumor cell and the stage of the cancer progression. Research to date suggests use of monoclonal antibodies against different CD44 variant isoforms and targeted inhibition of HA/CD44-mediated signaling combined with conventional radio/chemotherapy may be the most favorable therapeutic strategy for future treatments of advanced stage malignancies. Thus, this paper briefly focuses on the association of the major CD44 variant isoforms in cancer progression, the role of HA-CD44 interaction in oncogenic pathways, and strategies to target CD44-overexpressed tumor cells.

Published
2016
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8. Gene Expression Differences Predict Treatment Outcome of Merkel Cell Carcinoma Patients

Author

Loren Masterson, Bryan J. Thibodeau, Laura E. Fortier, Timothy J. Geddes, Barbara L. Pruetz, Rajwant Malhotra, Richard Keidan, and George D. Wilson

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Due to the rarity of Merkel cell carcinoma (MCC), prospective clinical trials have not been practical. This study aimed to identify biomarkers with prognostic significance. While sixty-two patients were identified who were treated for MCC at our institution, only seventeen patients had adequate formalin-fixed paraffin-embedded archival tissue and followup to be included in the study. Patients were stratified into good, moderate, or poor prognosis. Laser capture microdissection was used to isolate tumor cells for subsequent RNA isolation and gene expression analysis with Affymetrix GeneChip Human Exon 1.0 ST arrays. Among the 191 genes demonstrating significant differential expression between prognostic groups, keratin 20 and neurofilament protein have previously been identified in studies of MCC and were significantly upregulated in tumors from patients with a poor prognosis. Immunohistochemistry further established that keratin 20 was overexpressed in the poor prognosis tumors. In addition, novel genes of interest such as phospholipase A2 group X, kinesin family member 3A, tumor protein D52, mucin 1, and KIT were upregulated in specimens from patients with poor prognosis. Our pilot study identified several gene expression differences which could be used in the future as prognostic biomarkers in MCC patients.

Published
2014
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9. The Confluence of Stereotactic Ablative Radiotherapy and Tumor Immunology

Author

Steven Eric Finkelstein, Robert Timmerman, William H. McBride, Dörthe Schaue, Sarah E. Hoffe, Constantine A. Mantz, and George D. Wilson

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Stereotactic radiation approaches are gaining more popularity for the treatment of intracranial as well as extracranial tumors in organs such as the liver and lung. Technology, rather than biology, is driving the rapid adoption of stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), in the clinic due to advances in precise positioning and targeting. Dramatic improvements in tumor control have been demonstrated; however, our knowledge of normal tissue biology response mechanisms to large fraction sizes is lacking. Herein, we will discuss how SABR can induce cellular expression of MHC I, adhesion molecules, costimulatory molecules, heat shock proteins, inflammatory mediators, immunomodulatory cytokines, and death receptors to enhance antitumor immune responses.

Published
2011
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12. Data from Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma

Author

Prakash Chinnaiyan, C. Ryan Miller, George D. Wilson, Katie L. Buelow, Stewart F. Graham, Praveen Kumar, Shiva Kant, Antony Prabhu, and Pravin Kesarwani

Abstract

Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments.Results: Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood–brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation.Conclusions: Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression. Clin Cancer Res; 24(15); 3632–43. ©2018 AACR.

Published
2023
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15. Roadmap for Precision preclinical x-ray radiation studies

Author

Frank Verhaegen, Karl T Butterworth, Anthony J Chalmers, Rob P Coppes, Dirk de Ruysscher, Sophie Dobiasch, John D Fenwick, Patrick V Granton, Stefan H J Heijmans, Mark A Hill, Constantinos Koumenis, Kirsten Lauber, Brian Marples, Katia Parodi, Lucas C G G Persoon, Nick Staut, Anna Subiel, Rianne D W Vaes, Stefan van Hoof, Ioannis L Verginadis, Jan J Wilkens, Kaye J Williams, George D Wilson, Ludwig J Dubois, Maastro clinic, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, Surgery, M-lab, RS: GROW - R2 - Basic and Translational Cancer Biology, and Precision Medicine

Subjects
irradiation, dosimetry, Radiological and Ultrasound Technology, translation, imaging, SDG 3 - Good Health and Well-being, Radiology Nuclear Medicine and imaging, preclinical, precision, Radiology, Nuclear Medicine and imaging, cancer models
Abstract

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.

Published
2023
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20. Evidence for Early Mesozoic diversification of Hypsimetopidae Nicholls, 1943 (Isopoda), with the description of a new genus from Andhra Pradesh and notes on threats to Indian cave environments

Author

George D Wilson and Shabuddin Shaik

Subjects
Aquatic Science
Abstract

A new phreatoicidean isopod, Speonastes venkataramanigen., sp. nov. is described from Borra Cave in northeastern Andhra Pradesh, India. This new taxon has features seen in most phreatoicideans such as ventrally projecting pleonal pleurae, but also has features characteristic of the hypogean family Hypsimetopidae, such as an elongated pleotelson with a medially rotating uropod that has protopodal denticles or denticulate setae opposing the denticulate margin of the pleotelson, as well as the distal article of the antennula being minute and the penultimate article elongated and somewhat inflated. Robustness-tested phylogenetic analyses of character data from exemplars from nearly all phreatoicidean genera and four non-phreatoicidean outgroups finds that this species is the earliest derived member of Hypsimetopidae. These analyses have substantial implications for both relationships among Phreatoicidea, but within the family as well. The body form of the Phreatoicidea basal to the hypsimetopid clade resembles the form seen in fossils or by recent taxa such as CrenisopusWilson & Keable, 1999. Ancestors of Speonastesgen. nov. may have independently colonized India from those of the Nichollsia-Andhracoides clade. An early Mesozoic diversification of Hypsimetopidae and related taxa along continental rifts in eastern Gondwana between Antarctica, India, and Australia is one implication of the phylogeny. Although the caves of Andhra Pradesh and other Indian states have biologically unique and scientifically important taxa, India provides no protection for any cave. This exposes the fauna to negative impacts such as quarrying or illegal mining, over-exploitation of water resources, and damage from unconstrained tourist visitation.

Published
2022
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23. Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness

Author

Yize Li, Tung-Shing M. Lih, Saravana M. Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J. Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J. Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A. Wyczalkowski, Michael C. Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A. Reimers, Russell Pachynski, Alexander J. Lazar, Arul M. Chinnaiyan, Brian A. Van Tine, Bing Zhang, Karin D. Rodland, Gad Getz, D.R. Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W. Marston Linehan, David Fenyö, Scott D. Jewell, Gilbert S. Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I. Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W. Chan, Christopher J. Ricketts, Alexey I. Nesvizhskii, Hui Zhang, Li Ding, Alicia Francis, Amanda G. Paulovich, Andrzej Antczak, Anthony Green, Antonio Colaprico, Ari Hakimi, Barb Pruetz, Barbara Hindenach, Birendra Kumar Yadav, Boris Reva, Brenda Fevrier-Sullivan, Brian J. Druker, Cezary Szczylik, Charles A. Goldthwaite, Chet Birger, Corbin D. Jones, Daniel C. Rohrer, Darlene Tansil, David Chesla, David Heiman, Elizabeth Duffy, Eri E. Schadt, Francesca Petralia, Gabriel Bromiński, Gabriela M. Quiroga-Garza, George D. Wilson, Ginny Xiaohe Li, Grace Zhao, Yi Hsiao, James Hsieh, Jan Lubiński, Jasmin Bavarva, Jasmine Huang, Jason Hafron, Jennifer Eschbacher, Jennifer Hon, Jesse Francis, John Freymann, Josh Vo, Joshua Wang, Justin Kirby, Kakhaber Zaalishvili, Karen A. Ketchum, Katherine A. Hoadley, Ki Sung Um, Liqun Qi, Marcin J. Domagalski, Matt Tobin, Maureen Dyer, Meenakshi Anurag, Melissa Borucki, Michael A. Gillette, Michael J. Birrer, Michael M. Ittmann, Michael H. Roehrl, Michael Schnaubelt, Michael Smith, Mina Fam, Nancy Roche, Negin Vatanian, Nicollette Maunganidze, Olga Potapova, Oxana V. Paklina, Pamela VanderKolk, Patricia Castro, Paweł Kurzawa, Pushpa Hariharan, Qin Li, Qing Kay Li, Rajiv Dhir, Ratna R. Thangudu, Rebecca Montgomery, Richard D. Smith, Sailaja Mareedu, Samuel H. Payne, Sandra Cerda, Sandra Cottingham, Sarah Haynes, Shankha Satpathy, Shannon Richey, Shilpi Singh, Shirley X. Tsang, Shuang Cai, Song Cao, Stacey Gabriel, Steven A. Carr, Tao Liu, Thomas Bauer, Toan Le, Xi S. Chen, Xu Zhang, Yvonne Shutack, and Zhen Zhang

Subjects
Cancer Research, Oncology
Abstract

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

Published
2023
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24. Proteogenomic Characterization of Pancreatic Ductal Adenocarcinoma

Author

Marcin J. Domagalski, Wen Jiang, Michael Smith, Li Ding, Michael Schnaubelt, Oxana Paklina, Gilbert S. Omenn, Magdalena Derejska, Karin D. Rodland, Johanna Gardner, Saravana M. Dhanasekaran, Pamela Grady, Pushpa Hariharan, David Mallery, Jesse Francis, Maciej Wiznerowicz, Eunkyung An, Nancy Roche, Ralph H. Hruban, Samuel H. Payne, Chen Huang, Olga Potapova, Gad Getz, Zhiao Shi, Shuai Guo, Oliver F. Bathe, Stacey Gabriel, Sandra Cottingham, Hui Zhang, Daniel Cui Zhou, Maureen Dyer, Houxiang Zhu, James Suh, Shuang Cai, Christopher R. Kinsinger, Felipe da Veiga Leprevost, Steven Chen, Chelsea J. Newton, Amanda G. Paulovich, Steven A. Carr, Melissa Borucki, Sandra Cerda, Troy Shelton, D. R. Mani, Tara Hiltke, Lijun Chen, Benjamin Haibe-Kains, Jiang Long, Ratna R. Thangudu, Arul M. Chinnaiyan, Mathangi Thiagarajan, Negin Vatanian, Peter Ronning, Thomas L. Bauer, Ki Sung Um, Christina Ayad, Seungyeul Yoo, Mitual Amin, Ruiyang Liu, Alicia Francis, Nikolay Gabrovski, Eric E. Schadt, Zhen Zhang, Alexey I. Nesvizhskii, Hariharan Easwaran, Huan Chen, Tao Liu, Elizabeth R. Duffy, Liwei Cao, Joshua M. Wang, Michael H.A. Roehrl, Antonio Colaprico, Ana I. Robles, Emily S. Boja, Rita Jui-Hsien Lu, Rodrigo Vargas Eguez, Yize Li, Jennifer M. Koziak, Wenke Liu, Weiming Yang, Arvind Singh Mer, Dana R. Valley, Sailaja Mareedu, Song Cao, Scott D. Jewell, William Bocik, Shilpi Singh, Yongchao Dou, Matthew A. Wyczalkowski, David Fenyö, Galen Hostetter, Liqun Qi, Wenyi Wang, Yvonne Shutack, Shirley Tsang, Karen A. Ketchum, Charles A. Goldthwaite, Katherine A. Hoadley, Richard D. Smith, Karsten Krug, Yuxing Liao, Nadezhda V. Terekhanova, Henry Rodriguez, Barbara Hindenach, Matthew J. Ellis, Yingwei Hu, Pei Wang, Daniel C. Rohrer, Sara R. Savage, Grace Zhao, Ludmila Danilova, Yige Wu, Parham Minoo, Jennifer M. Eschbacher, Nathan Edwards, T. Mamie Lih, Simina M. Boca, George D. Wilson, Alexey Shabunin, Bing Zhang, Michael A. Gillette, Brian J. Druker, David J. Clark, Jianbo Pan, Katarzyna Kusnierz, David Chesla, Ronald Matteotti, Corbin D. Jones, Michael J. Birrer, Lori J. Sokoll, Qing Kay Li, Mehdi Mesri, Peter B. McGarvey, Chet Birger, Barbara Pruetz, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, and Jasmine Huang

Subjects
Adult, Male, Pancreatic ductal adenocarcinoma, Proteome, Gene Dosage, Biology, Adenocarcinoma, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Substrate Specificity, Cohort Studies, medicine, Humans, Molecular Targeted Therapy, Phosphorylation, Aged, Glycoproteins, Proteogenomics, Aged, 80 and over, MicroRNA sequencing, Genome, Human, RNA, Endothelial Cells, Methylation, Middle Aged, Phosphoproteins, Prognosis, Pancreatic Neoplasms, Phenotype, Cancer research, Female, KRAS, Signal transduction, Carcinogenesis, Transcriptome, Glycolysis, Protein Kinases, Algorithms, Carcinoma, Pancreatic Ductal
Abstract

Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.

Published
2021

25. Intratumoural haematopoietic stem and progenitor cell differentiation into M2 macrophages facilitates the regrowth of solid tumours after radiation therapy

Author

Tyler M. Parsons, Katie L. Buelow, Alaa Hanna, Marisa A. Brake, Crystal Poma, Sarah E. Hosch, Randal J. Westrick, Luis G. Villa-Diaz, George D. Wilson, and Gerard J. Madlambayan

Subjects
Cancer Research, Mice, Oncology, Macrophages, Neoplasms, Tumor Microenvironment, Animals, Humans, Cell Differentiation, Hematopoietic Stem Cells, Article
Abstract

BACKGROUND: Bone-marrow-derived haematopoietic stem and progenitor cells (HSPCs) are a prominent part of the highly complex tumour microenvironment (TME) where they localise within tumours and maintain haematopoietic potency. Understanding the role HSPCs play in tumour growth and response to radiation therapy (RT) may lead to improved patient treatments and outcomes. METHODS: We used a mouse model of non-small cell lung carcinoma where tumours were exposed to RT regimens alone or in combination with GW2580, a pharmacological inhibitor of colony stimulating factor (CSF)-1 receptor. RT-PCR, western blotting and immunohistochemistry were used to quantify expression levels of factors that affect HSPC differentiation. DsRed(+) HSPC intratumoural activity was tracked using flow cytometry and confocal microscopy. RESULTS: We demonstrated that CSF-1 is enhanced in the TME following exposure to RT. CSF-1 signaling induced intratumoural HSPC differentiation into M2 polarised tumour-associated macrophages (TAMs), aiding in post-RT tumour survival and regrowth. In contrast, hyperfractionated/pulsed radiation therapy (PRT) and GW2580 ablated this process resulting in improved tumour killing and mouse survival. CONCLUSIONS: Tumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours.

Published
2021

26. Proteogenomic and metabolomic characterization of human glioblastoma

Author

Cristina E. Tognon, Larisa Polonskaya, Tara Skelly, Shuang Cai, Francesmary Modugno, Larissa Rossell, Nancy Roche, Chen Huang, Jessika Baral, Fulvio D'Angelo, Wen-Wei Liang, Chia-Feng Tsai, Sneha P. Couvillion, Karin D. Rodland, Jun Zhu, Liang-Bo Wang, Paul D. Piehowski, Antonio Colaprico, Anupriya Agarwal, Matthew A. Wyczalkowski, Umut Ozbek, Francesca Petralia, Alexis Demopoulos, William W. Maggio, Lin Chen, Katherine A. Hoadley, Richard D. Smith, Sandra Cottingham, John McGee, Marcin J. Domagalski, Houxiang Zhu, Emek Demir, Rebecca I. Montgomery, Jamie Moon, Rashna Madan, George D. Wilson, Luciano Garofano, Ewa P. Malc, Chelsea J. Newton, Steven A. Carr, Chandan Kumar-Sinha, Donghui Tan, Christopher R. Kinsinger, Oxana Paklina, Weiqing Wan, Stephanie De Young, Sandra Cerda, Shankha Satpathy, Wojciech Kaspera, Linda Hannick, Gad Getz, Runyu Hong, Shuangjia Lu, Ziad Hanhan, Daniel C. Rohrer, Annette Marrero-Oliveras, Wojciech Szopa, Yuxing Liao, Amanda G. Paulovich, Jiayi Ji, Denis A. Golbin, Tara Hiltke, Weiva Sieh, Piotr A. Mieczkowski, Matthew E. Monroe, Gilbert S. Omenn, Jill S. Barnholtz-Sloan, Azra Krek, Bing Zhang, Brittany Henderson, Peter B. McGarvey, Ratna R. Thangudu, Maciej Wiznerowicz, Saravana M. Dhanasekaran, Alex Webster, Kai Li, Karna Robinson, Nan Ji, Karl K. Weitz, Simina M. Boca, Xiaoyu Song, Anna Calinawan, Adam C. Resnick, Brian J. Druker, Dana R. Valley, David J. Clark, Tao Liu, Eric J. Jaehnig, Alicia Francis, Michele Ceccarelli, Rui Zhao, Dmitry Rykunov, Boris Reva, Elizabeth R. Duffy, Antonio Iavarone, Dave Tabor, Joshua F. McMichael, Daniel Cui Zhou, Maureen Dyer, Kimberly Elburn, Scott D. Jewell, Negin Vatanian, Shirley Tsang, Seungyeul Yoo, Alexander R. Pico, Grace Zhao, Kent J. Bloodsworth, Chet Birger, Jena Lilly, Eunkyung An, Jeffrey R. Whiteaker, Albert H. Kim, Yige Wu, Karen A. Ketchum, Felipe D. Leprevost, Alcida Karz, Uma Borate, Nathan Edwards, Uma Velvulou, Melissa Borucki, Vasileios Stathias, Sanford P. Markey, Corbin D. Jones, Ronald J. Moore, MacIntosh Cornwell, Karsten Krug, Michael J. Birrer, James Suh, Tomasz Czernicki, Jason E. McDermott, Emily S. Boja, Pei Wang, Nina Martinez, Wenke Liu, Yan Shi, Lili Blumenberg, Emily Kawaler, Jeffrey W. Tyner, Feng Chen, Jakub Stawicki, Ki Sung Um, Arul M. Chinnaiyan, Robert Zelt, Jacob J. Day, Zhen Zhang, Caleb M. Lindgren, Li Ding, Nikolay Gabrovski, Hongwei Liu, Jonathan T. Lei, Alla Karpova, Ramani B. Kothadia, Sailaja Mareedu, Mitual Amin, Hannah Boekweg, Jennifer E. Kyle, Sara R. Savage, Brian R. Rood, Yuriy Zakhartsev, Matthew L. Anderson, Alyssa Charamut, Wagma Caravan, Shakti Ramkissoon, Junmei Wang, Song Cao, Samuel H. Payne, Rosalie K. Chu, Rajiv Dhir, David W. Andrews, Galen Hostetter, Liqun Qi, Zhiao Shi, Milan G. Chheda, Robert Edwards, Hui Zhang, Weiping Ma, Jennifer M. Eschbacher, Stacey Gabriel, Jan Lubinski, Lijun Yao, Erika M. Zink, Kelly L. Stratton, William Bocik, Mathangi Thiagarajan, Shilpi Singh, Michael A. Gillette, Lisa M. Bramer, Thomas L. Bauer, Michael Vernon, Henry Rodriguez, Dimitris G. Placantonakis, Eric E. Schadt, Alexey I. Nesvizhskii, Vladislav A. Petyuk, Ana I. Robles, Yvonne Shutack, Anna Malovannaya, Stephen E. Stein, Xi Chen, Lyndon Kim, Yize Li, Shannon Richey, Stephan C. Schürer, Barbara Hindenach, Matthew J. Ellis, Yongchao Dou, David Fenyö, Amy M. Perou, Olga Potapova, Shrabanti Chowdhury, Andrew K. Godwin, Marcin Cieślik, Michael C. Wendl, Marina A. Gritsenko, Pietro Pugliese, Elie Traer, Simona Migliozzi, D. R. Mani, Houston Culpepper, Gregory J. Riggins, Xiaolu Yang, Mehdi Mesri, David Chesla, Lindsey K. Olsen, Lori J. Sokoll, Suhas Vasaikar, Liwei Zhang, Meghan C. Burke, Kelly V. Ruggles, Qing Kay Li, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Darlene Tansil, Joseph H. Rothstein, Barbara Pruetz, Pushpa Hariharan, Wang, L. -B., Karpova, A., Gritsenko, M. A., Kyle, J. E., Cao, S., Li, Y., Rykunov, D., Colaprico, A., Rothstein, J. H., Hong, R., Stathias, V., Cornwell, M., Petralia, F., Wu, Y., Reva, B., Krug, K., Pugliese, P., Kawaler, E., Olsen, L. K., Liang, W. -W., Song, X., Dou, Y., Wendl, M. C., Caravan, W., Liu, W., Cui Zhou, D., Ji, J., Tsai, C. -F., Petyuk, V. A., Moon, J., Ma, W., Chu, R. K., Weitz, K. K., Moore, R. J., Monroe, M. E., Zhao, R., Yang, X., Yoo, S., Krek, A., Demopoulos, A., Zhu, H., Wyczalkowski, M. A., Mcmichael, J. F., Henderson, B. L., Lindgren, C. M., Boekweg, H., Lu, S., Baral, J., Yao, L., Stratton, K. G., Bramer, L. M., Zink, E., Couvillion, S. P., Bloodsworth, K. J., Satpathy, S., Sieh, W., Boca, S. M., Schurer, S., Chen, F., Wiznerowicz, M., Ketchum, K. A., Boja, E. S., Kinsinger, C. R., Robles, A. I., Hiltke, T., Thiagarajan, M., Nesvizhskii, A. I., Zhang, B., Mani, D. R., Ceccarelli, M., Chen, X. S., Cottingham, S. L., Li, Q. K., Kim, A. H., Fenyo, D., Ruggles, K. V., Rodriguez, H., Mesri, M., Payne, S. H., Resnick, A. C., Wang, P., Smith, R. D., Iavarone, A., Chheda, M. G., Barnholtz-Sloan, J. S., Rodland, K. D., Liu, T., Ding, L., Agarwal, A., Amin, M., An, E., Anderson, M. L., Andrews, D. W., Bauer, T., Birger, C., Birrer, M. J., Blumenberg, L., Bocik, W. E., Borate, U., Borucki, M., Burke, M. C., Cai, S., Calinawan, A. P., Carr, S. A., Cerda, S., Chan, D. W., Charamut, A., Chen, L. S., Chesla, D., Chinnaiyan, A. M., Chowdhury, S., Cieslik, M. P., Clark, D. J., Culpepper, H., Czernicki, T., D'Angelo, F., Day, J., De Young, S., Demir, E., Dhanasekaran, S. M., Dhir, R., Domagalski, M. J., Druker, B., Duffy, E., Dyer, M., Edwards, N. J., Edwards, R., Elburn, K., Ellis, M. J., Eschbacher, J., Francis, A., Gabriel, S., Gabrovski, N., Garofano, L., Getz, G., Gillette, M. A., Godwin, A. K., Golbin, D., Hanhan, Z., Hannick, L. I., Hariharan, P., Hindenach, B., Hoadley, K. A., Hostetter, G., Huang, C., Jaehnig, E., Jewell, S. D., Ji, N., Jones, C. D., Karz, A., Kaspera, W., Kim, L., Kothadia, R. B., Kumar-Sinha, C., Lei, J., Leprevost, F. D., Li, K., Liao, Y., Lilly, J., Liu, H., Lubinski, J., Madan, R., Maggio, W., Malc, E., Malovannaya, A., Mareedu, S., Markey, S. P., Marrero-Oliveras, A., Martinez, N., Maunganidze, N., Mcdermott, J. E., Mcgarvey, P. B., Mcgee, J., Mieczkowski, P., Migliozzi, S., Modugno, F., Montgomery, R., Newton, C. J., Omenn, G. S., Ozbek, U., Paklina, O. V., Paulovich, A. G., Perou, A. M., Pico, A. R., Piehowski, P. D., Placantonakis, D. G., Polonskaya, L., Potapova, O., Pruetz, B., Qi, L., Ramkissoon, S., Resnick, A., Richey, S., Riggins, G., Robinson, K., Roche, N., Rohrer, D. C., Rood, B. R., Rossell, L., Savage, S. R., Schadt, E. E., Shi, Y., Shi, Z., Shutack, Y., Singh, S., Skelly, T., Sokoll, L. J., Stawicki, J., Stein, S. E., Suh, J., Szopa, W., Tabor, D., Tan, D., Tansil, D., Thangudu, R. R., Tognon, C., Traer, E., Tsang, S., Tyner, J., Um, K. S., Valley, D. R., Vasaikar, S., Vatanian, N., Velvulou, U., Vernon, M., Wan, W., Wang, J., Webster, A., Wen, B., Whiteaker, J. R., Wilson, G. D., Zakhartsev, Y., Zelt, R., Zhang, H., Zhang, L., Zhang, Z., Zhao, G., and Zhu, J.

Subjects
Proteomics, 0301 basic medicine, Cancer Research, CPTAC, Histone H2B acetylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Computational biology, Biology, Article, 03 medical and health sciences, lipidome, 0302 clinical medicine, Metabolomics, proteogenomic, Humans, Phosphorylation, EP300, proteomic, Proteogenomics, acetylome, single nuclei RNA-seq, Brain Neoplasms, Phospholipase C gamma, glioblastoma, Computational Biology, Lipidome, 030104 developmental biology, Histone, Oncology, Acetylation, 030220 oncology & carcinogenesis, Mutation, biology.protein, metabolome, signaling
Abstract

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.

Published
2021

27. A proteogenomic portrait of lung squamous cell carcinoma

Author

Shuang Cai, Elizabeth R. Duffy, Felipe da Veiga Leprevost, D. R. Mani, Antonio Colaprico, Jiayi Ji, Mehdi Mesri, Alicia Francis, Peter B. McGarvey, Myvizhi Esai Selvan, Corbin D. Jones, Michael J. Birrer, Robert J. Welsh, Lori Bernard, Shankha Satpathy, Li Ding, Sara R. Savage, Eugene S. Fedorov, Fernanda Martins Rodrigues, Marcin J. Domagalski, Jennifer M. Eschbacher, Shayan C. Avanessian, Boris Reva, Harsh Batra, Suhas Vasaikar, Nathan Edwards, Michael A. Gillette, Chet Birger, Scott D. Jewell, Kei Suzuki, William Bocik, Shilpi Singh, Meenakshi Anurag, Karen E. Christianson, Namrata D. Udeshi, Vasileios Stathias, Warren G. Tourtellotte, Karl R. Clauser, Shutack, Andrii Karnuta, Dana R. Valley, Kelly V. Ruggles, Qing Kay Li, Amanda G. Paulovich, MacIntosh Cornwell, Shankara Anand, Bartosz Kubisa, Pierre M. Jean Beltran, James Suh, Gilbert S. Omenn, Azra Krek, Wohaib Hasan, Yongchao Dou, David Fenyö, Henry Rodriguez, Samuel H. Payne, Małgorzata Wojtyś, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Özgün Babur, Renganayaki Pandurengan, Karen A. Ketchum, Nikolay Gabrovski, Pankaj Vats, Saravana M. Dhanasekaran, Richard D. Smith, Gad Getz, Sailaja Mareedu, Yuxing Liao, Mikhail Krotevich, Hui Zhang, Eric J. Jaehnig, Charles A. Goldthwaite, Alexey I. Nesvizhskii, Katherine A. Hoadley, Alexander A. Green, Francesca Petralia, Chandan Kumar-Sinha, Karsten Krug, Eunkyung An, Elena V. Ponomareva, Ximing Tang, Nancy Roche, Daniel C. Rohrer, David I. Heiman, Arul M. Chinnaiyan, Pamela Grady, Rebecca I. Montgomery, Galen Hostetter, Liqun Qi, Stephan C. Schürer, George D. Wilson, Pushpa Hariharan, Zhen Zhang, Yvonne, David Chesla, Chia-Kuei Mo, Maria Gabriela Raso, Negin Vatanian, Paul K. Paik, Fei Ding, Thomas L. Bauer, Barbara Hindenach, Matthew J. Ellis, Chen Huang, Karin D. Rodland, Oluwole Fadare, Ramaswamy Govindan, Eric E. Schadt, Sandra Cottingham, Barbara Pruetz, Sendurai A. Mani, Shirley Tsang, Carissa Huynh, Weiping Ma, Jennifer E. Maas, Tobias Schraink, Stacey Gabriel, Bing Zhang, Tara Hiltke, Rama Soundararajan, Tatiana Omelchenko, Brian J. Druker, Matthew A. Wyczalkowski, Neil R. Mucci, Ziad Hanhan, Donna E. Hansel, Yifat Geffen, Mathangi Thiagarajan, Xiaojun Jing, Pei Wang, Alfredo Molinolo, Tanmayi Vashist, Ratna R. Thangudu, Maciej Wiznerowicz, Edwin R. Parra, Tanvi H. Visal, Maureen Dyer, Melissa Borucki, Ki Sung Um, Jonathan T. Lei, Marcin Cieslik, Christopher R. Kinsinger, M. Harry Kane, Houxiang Zhu, Chelsea J. Newton, Steven A. Carr, Tao Liu, Wenke Liu, Volodymyr Sovenko, Olga Potapova, Eric J. Burks, Song Cao, Ana I. Robles, Yuping Zhang, Yize Li, Midie Xu, Erik J. Bergstrom, Zeynep H. Gümüş, Kai Li, and Xiaoyu Song

Subjects
Adult, Male, Epithelial-Mesenchymal Transition, Lung Neoplasms, Biology, Proteomics, Receptor Tyrosine Kinase-like Orphan Receptors, General Biochemistry, Genetics and Molecular Biology, Article, SOX2, CDKN2A, Survivin, medicine, Cluster Analysis, Humans, Receptors, Platelet-Derived Growth Factor, Phosphorylation, Lung cancer, Aged, Proteogenomics, Aged, 80 and over, EZH2, Ubiquitination, Cyclin-Dependent Kinase 4, Acetylation, Cyclin-Dependent Kinase 6, Middle Aged, medicine.disease, Chromatin, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, Protein Binding, Signal Transduction
Abstract

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.

Published
2020

28. Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Author

Yuxing Liao, Meghan C. Burke, Donghui Tan, Xiaoyu Song, Lauren C. Tang, Elizabeth R. Duffy, Shayan C. Avanessian, Daniel Cui Zhou, Maureen Dyer, Sara R. Savage, Jennifer M. Eschbacher, Shaleigh Smith, Alex Webster, Alicia Francis, Kelly V. Ruggles, Christopher R. Kinsinger, Shirley Tsang, Melissa Borucki, Nancy Roche, Pei Wang, Qing Kay Li, David Chesla, Ronald Matteotti, Zeynep H. Gümüş, Kai Li, Kei Suzuki, Thomas L. Bauer, Lori J. Sokoll, John McGee, Marcin J. Domagalski, Ki Sung Um, Tara Hiltke, Hai-Quan Chen, Hongwei Liu, Eric E. Schadt, Antonio Colaprico, Alyssa Charamut, Lijun Chen, Emily Kawaler, Ramani B. Kothadia, Mehdi Mesri, Jiayi Ji, Simina M. Boca, Myvizhi Esai Selvan, Emily S. Boja, Xi Chen, Shuang Cai, Kim Elburn, Samuel H. Payne, George D. Wilson, Peter B. McGarvey, Chelsea J. Newton, Felipe da Veiga Leprevost, Uma Velvulou, Tara Skelly, Corbin D. Jones, Michael J. Birrer, Steven A. Carr, Erik J. Bergstrom, Jeffrey R. Whiteaker, Michael H.A. Roehrl, Gad Getz, Tanya Krubit, Zhen Zhang, Yan Shi, Lili Blumenberg, Melanie A. MacMullan, Song Cao, Zhiao Shi, Weiping Ma, Chet Birger, Karl R. Clauser, Runyu Hong, Shankha Satpathy, Andrii Karnuta, Boris Reva, Barbara Hindenach, Matthew J. Ellis, Amanda G. Paulovich, Michael C. Wendl, Bing Zhang, Marina A. Gritsenko, Matthew A. Wyczalkowski, Stacey Gabriel, Michael A. Gillette, Jacob J. Day, Maciej Wiznerowicz, Stephen E. Stein, Ewa P. Malc, Robert J. Welsh, Sunita Shankar, Brian J. Druker, Li Ding, Lijun Yao, David J. Clark, Małgorzata Wojtyś, Dmitry Rykunov, Eugene S. Fedorov, Linda Hannick, Andrew K. Godwin, Sailaja Mareedu, Pushpa Hariharan, Mary Beth Beasley, Stephanie De Young, Arul M. Chinnaiyan, Robert Zelt, Mathangi Thiagarajan, Munziba Khan, Suhas Vasaikar, Tao Liu, Karin D. Rodland, Katherine A. Hoadley, Wen-Wei Liang, Ana I. Robles, Dana R. Valley, Sanford P. Markey, Mikhail Krotevich, David I. Heiman, Piotr A. Mieczkowski, Galen Hostetter, Liqun Qi, Yige Wu, Hui Zhang, Liang-Bo Wang, Nathan Edwards, Ramaswamy Govindan, Yifat Geffen, Seema Chugh, Alexey I. Nesvizhskii, Karen A. Ketchum, Pankaj Vats, Matthew E. Monroe, Marcin Cieslik, Yingwei Hu, Karsten Krug, Yosef E. Maruvka, Yize Li, Ratna R. Thangudu, William W. Maggio, Sandra Cottingham, Saravana M. Dhanasekaran, Wenke Liu, Hua Sun, Sonya Carter, Volodymyr Sovenko, M. Harry Kane, Annette Marrero-Oliveras, Barbara Pruetz, Amy M. Perou, Gilbert S. Omenn, Azra Krek, Olga Potapova, Michael S. Noble, Daniel W. Chan, Seungyeul Yoo, Eric J. Burks, Bo Wen, William Bocik, Michael Vernon, Henry Rodriguez, James Suh, Scott D. Jewell, MacIntosh Cornwell, Richard D. Smith, Chandan Kumar-Sinha, Halina M. Krzystek, Daniel C. Rohrer, Tatiana Omelchenko, D. R. Mani, Houston Culpepper, Vladislav A. Petyuk, Meng-Hong Sun, Michelle Chaikin, David Fenyö, Rahul Mannan, Bartosz Kubisa, Rohit Mehra, Rajwanth R. Veluswamy, Umut Ozbek, Michael Schnaubelt, Francesca Petralia, Elena V. Ponomareva, Rashna Madan, Pamela Grady, Karna Robinson, and Negin Vatanian

Subjects
0303 health sciences, Phosphoproteomics, Genomics, Environmental exposure, Computational biology, Biology, Proteomics, Proteogenomics, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Neutrophil degranulation, medicine, KRAS, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics
Abstract

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.

Published
2020
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29. Tumor Voxel Dose-Response Matrix and Dose Prescription Function Derived Using

Author

Di, Yan, Shupeng, Chen, Daniel J, Krauss, Peter Y, Chen, Prakash, Chinnaiyan, and George D, Wilson

Subjects
Fluorodeoxyglucose F18, Head and Neck Neoplasms, Positron Emission Tomography Computed Tomography, Carcinoma, Squamous Cell, Feasibility Studies, Humans, Dose-Response Relationship, Radiation, Radiotherapy Dosage, Chemoradiotherapy, Radiopharmaceuticals, Radiation Tolerance
Abstract

To construct a tumor voxel dose response matrix (DRM) and dose prescription function (DPF) for adaptive dose painting by number (DPbN) based on treatment feedback of fluoro-2-deoxyglucose (FGD) positron emission tomography (PET)/computed tomography (CT) imaging.FDG-PET/CT images obtained before and after chemoradiation therapy and at weekly chemoradiation therapy sessions for each of 18 patients with head and neck cancer, as well as the treatment outcomes, were used in the modeling. All weekly and posttreatment PET/CT images were registered voxel-to-voxel to the corresponding pretreatment baseline PET/CT image. Tumor voxel DRM was created using serial FDG-PET imaging of each patient with respect to the baseline standardized uptake value (SUVLarge intertumoral and intratumoral variations on both tumor voxels (SUVTumor voxel (SUV

Published
2018

30. Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans

Author

Nora Franceschini, Oscar H. Franco, Laura J. Bierut, John P. Rice, Kenneth Rice, Sarah Bertelsen, Donna K. Arnett, Michael R. Brown, Lynda M. Rose, J. C. Wang, Louis Fox, A.G. Uitterlinden, George D. Wilson, B. Marosy, Lei Chen, Nancy L. Saccone, Alanna C. Morrison, R. G. Barr, Dina Vojinovic, Bruce M. Psaty, Najaf Amin, A. Hofman, Jerry A. Stitzel, Eric O. Johnson, Kurt N. Hetrick, Karen Schwander, Rob Culverhouse, Traci M. Bartz, Ervin R. Fox, Cathy C. Laurie, Jie Yao, Sharon L.R. Kardia, Dorothy K. Hatsukami, Ursula M. Schick, Wei Zhao, Mary F. Feitosa, C M van Duijn, Alison Goate, Megan L. Grove, Naomi Breslau, Alexander P. Reiner, Sarah M. Hartz, Stephanie M. Gogarten, Steven M. Foltz, Paul M. Ridker, Xiuqing Guo, Erin B. Ware, Daniel I. Chasman, Dabeeru C. Rao, Solomon K. Musani, Emily Olfson, Kimberly F. Doheny, Ingrid B. Borecki, Epidemiology, and Internal Medicine

Subjects
Adult, Male, 0301 basic medicine, Fagerstrom Test for Nicotine Dependence, Nonsynonymous substitution, Nerve Tissue Proteins, Receptors, Nicotinic, White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, Molecular Biology, Exome, Genetics, biology, business.industry, CHRNA5, Genetic Variation, Tobacco Use Disorder, Odds ratio, Middle Aged, Black or African American, Minor allele frequency, Psychiatry and Mental health, 030104 developmental biology, Meta-analysis, biology.protein, Female, business, 030217 neurology & neurosurgery
Abstract

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstrom Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF

Published
2015
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31. Proteogenomic Characterization of Endometrial Carcinoma

Author

David J. Clark, Jiayi Ji, Beom-Jun Kim, Doug W. Chan, Zhen Zhang, Kim Elburn, Munziba Khan, Katherine Fuh, Katherine A. Hoadley, Jeffrey R. Whiteaker, Peter B. McGarvey, Dana R. Valley, Douglas A. Levine, Sanford P. Markey, Hui Zhang, Tanya Krubit, Christopher R. Kinsinger, Hui Yin Chang, Yuxing Liao, Karen A. Ketchum, Piotr A. Mieczkowski, Pankaj Vats, Matthew E. Monroe, Donghui Tan, Alex Webster, Chet Birger, Kai Li, Ramani Kothadia, Saravana M. Dhanasekaran, Sara R. Savage, Karsten Krug, Marcin Jędryka, Matthew L. Anderson, Alyssa Charamut, Alexander R. Pico, Amanda G. Paulovich, Karna Robinson, Hua Zhou, John McGee, Sean J.I. Beecroft, Amanda E. Oliphant, Annette Marrero-Oliveras, Dmitry Rykunov, Shuang Cai, Francesmary Modugno, Marcin J. Domagalski, Emily Kawaler, Mehdi Mesri, Dmitry M. Avtonomov, Milan G. Chheda, Sue Hilsenbeck, Gilbert S. Omenn, Emek Demir, Rebecca I. Montgomery, Qingsong Gao, Azra Krek, Eric E. Schadt, Li Ding, George D. Wilson, Stephen E. Stein, David Chesla, Gad Getz, Negin Vatanian, Thomas F. Westbrook, Deborah DeLair, David I. Heiman, Karl R. Clauser, Rafal Matkowski, Lori J. Sokoll, Uma Borate, Antonio Colaprico, Jin Chen, Eric J. Jaehnig, Karin D. Rodland, Richard D. Smith, Linda Hannick, Uma Velvulou, Shannon Richey, Andrzej Czekański, Bing Zhang, Arul M. Chinnaiyan, Robert Zelt, Daniel J. Geiszler, Emily L. Hoskins, Ronald J. Moore, Pushpa Hariharan, Suhas Vasaikar, Jason E. McDermott, Yige Wu, Anna Malovannaya, Brian J. Druker, Jeffrey W. Tyner, Yan Shi, Lili Blumenberg, Jamie Moon, Cristina E. Tognon, Chandan Kumar-Sinha, Nathan Edwards, Yifat Geffen, Barbara Hindenach, Matthew J. Ellis, Zhi Li, Michael Schnaubelt, David C. Wheeler, Tara Skelly, Ewa P. Malc, Shrabanti Chowdhury, Andrew K. Godwin, Zhiao Shi, Francesca Petralia, Lin Chen, Scott D. Jewell, Daniel C. Rohrer, Elie Traer, Michael Ittmann, Shankha Satpathy, Marcin Cieslik, Weiping Ma, Daniel Cui Zhou, Maureen Dyer, Boris Reva, Rashna Madan, William Bocik, Stacey Gabriel, Stephanie De Young, Yosef E. Maruvka, Sandra Cottingham, Pamela Grady, D. R. Mani, Houston Culpepper, Meenakshi Anurag, Michael T. Lewis, Anupriya Agarwal, Felipe D. Leprevost, Jonathan C. Jarman, Michael Vernon, Henry Rodriguez, Matthew A. Wyczalkowski, Rui Zhao, Vladislav A. Petyuk, Michelle Chaikin, James Suh, Daniel W. Chan, Bo Wen, Patricia Castro, Alexey I. Nesvizhskii, Chia-Feng Tsai, Grace Zhao, Alicia Francis, Feng Chen, Mathangi Thiagarajan, Pei Wang, Marina A. Gritsenko, Anna Calinawan, David G. Mutch, Melissa Borucki, Xi Steven Chen, Guo Ci Teo, Peter Dottino, Corbin D. Jones, Michael J. Birrer, Ying Wang, Meghan C. Burke, MacIntosh Cornwell, Song Cao, Rosalie K. Chu, Larisa Polonskaya, Samuel H. Payne, Darlene Tansil, Yongchao Dou, David Fenyö, Kelly V. Ruggles, Qing Kay Li, Yuping Zhang, James J. Hsieh, Andy T. Kong, Ana I. Robles, Emily S. Boja, Chelsea J. Newton, Steven A. Carr, Sandra Cerda, Runyu Hong, Jacob J. Day, Sailaja Mareedu, Jan Lubinski, Galen Hostetter, Liqun Qi, Yize Li, Chen Huang, Liang-Bo Wang, Tao Liu, Renee Karabon, Paul D. Piehowski, Samuel L. Pugh, Maciej Wiznerowicz, Ratna R. Thangudu, Wenke Liu, Jayson B. Field, Sonya Carter, Ki Sung Um, Hongwei Liu, Alla Karpova, Yuriy Zakhartsev, Amy M. Perou, Michael S. Noble, Rajiv Dhir, Nancy Roche, Sunantha Sethuraman, Tara Hiltke, Lijun Chen, Xiaoyu Song, Elizabeth R. Duffy, Robert Edwards, Yingwei Hu, John A. Martignetti, Simina M. Boca, Michael A. Gillette, and David W Adams

Subjects
Epithelial-Mesenchymal Transition, Proteome, Druggability, Biology, Proteomics, Genomic Instability, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigens, Neoplasm, medicine, Animals, Humans, Phosphorylation, 030304 developmental biology, Feedback, Physiological, 0303 health sciences, Endometrial cancer, Carcinoma, Wnt signaling pathway, Cancer, Acetylation, medicine.disease, Proteogenomics, Endometrial Neoplasms, Gene Expression Regulation, Neoplastic, MicroRNAs, Serous fluid, Histone, Cancer research, biology.protein, Female, Transcriptome, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Microsatellite Repeats, Signal Transduction
Abstract

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

Published
2020
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32. Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

Author

David J. Clark, Jianbo Pan, Gerald W. Hart, Katherine A. Hoadley, Negin Vatanian, Shuang Cai, Yige Wu, Felipe da Veiga Leprevost, A. Ari Hakimi, Sanford P. Markey, Thomas F. Westbrook, Maciej Wiznerowicz, Nathan Edwards, Alla Y. Karpova, Sohini Sengupta, Marcin Cieslik, Samuel H. Payne, Xi Steven Chen, Guo Ci Teo, Jin Chen, Boris Reva, Corbin D. Jones, Michael J. Birrer, Ying Wang, Kelly V. Ruggles, Doug W. Chan, John McGee, Marcin J. Domagalski, Song Cao, Linda Hannick, Christopher R. Kinsinger, David I. Heiman, Jennifer M. Eschbacher, Munziba Khan, Jason E. McDermott, Dmitry M. Avtonomov, Sue Hilsenbeck, Qing Kay Li, Jiayi Ji, Emek Demir, Rebecca I. Montgomery, Qingsong Gao, Beom-Jun Kim, Xiaoyu Song, Karl R. Clauser, Christian P. Pavlovich, Richard D. Smith, Maureen Dyer, Jeffrey W. Tyner, Amy M. Perou, Yuping Zhang, Dana R. Valley, George D. Wilson, Shiyong Ma, Minghui Ao, Jiang Qian, Umut Ozbek, Melissa Borucki, Zhi Li, Michael Schnaubelt, Chen Huang, Piotr A. Mieczkowski, Francesca Petralia, Abdul Samad Hashimi, Hui Yin Chang, Liang-Bo Wang, Matthew E. Monroe, Peter B. McGarvey, Tao Liu, Karen A. Ketchum, Hui Zhang, Bing Zhang, D. R. Mani, Houston Culpepper, Hua Zhou, Saravana M. Dhanasekaran, Paul D. Piehowski, Zhidong Tu, Brian J. Druker, Ki Sung Um, Zhiao Shi, Uma Borate, Uma Velvulou, Michael Ittmann, Weiping Ma, Steven M. Foltz, Heng Zhu, Stacey Gabriel, Hongwei Liu, Ramani B. Kothadia, Lin Chen, Ewa P. Malc, Marina A. Gritsenko, Jun Zhu, David Chesla, Lori J. Sokoll, Stephen E. Stein, Andrzej Antczak, Matthew L. Anderson, Alyssa Charamut, Pamela Grady, Michael T. Lewis, Shannon Richey, Tanya Krubit, Alexander R. Pico, Kyung-Cho Cho, Daniel C. Rohrer, Francesmary Modugno, Stephanie De Young, Li Ding, Michael Smith, Mathangi Thiagarajan, Alexey I. Nesvizhskii, Shrabanti Chowdhury, Noam D. Beckmann, Kimberly R. Holloway, Ratna R. Thangudu, Sherri R. Davies, Tung-Shing M. Lih, Nicole Tignor, Anna Calinawan, Meghan C. Burke, Karna Robinson, Chet Birger, Shalin Patel, Antonio Colaprico, Sarah Keegan, Daniel J. Geiszler, Scott D. Jewell, William Bocik, Snehal Patil, Pei Wang, MacIntosh Cornwell, Emily Kawaler, Seungyeul Yoo, Jasmine Huang, Vladislav A. Petyuk, Ross Bremner, Donghui Tan, Stefani N. Thomas, Emily S. Boja, Anna Malovannaya, Xi Chen, Wenke Liu, Eric E. Schadt, Shankha Satpathy, Nancy Roche, Rajiv Dhir, Cristina E. Tognon, Michelle Chaikin, Gabriel Bromiński, Daniel C. Zhou, Yifat Geffen, Tara Skelly, Jacob J. Day, Sunantha Sethuraman, Sonya Carter, Zhen Zhang, Selim Kalayci, Michael Vernon, Zeynep H. Gümüş, Kai Li, Barbara Hindenach, Matthew J. Ellis, Meenakshi Anurag, David C. Wheeler, Sailaja Mareedu, Andy T. Kong, Arul M. Chinnaiyan, Robert Zelt, Annette Marrero-Oliveras, Henry Rodriguez, James Suh, Anupriya Agarwal, David Fenyö, Galen Hostetter, Liqun Qi, Matthew A. Wyczalkowski, W. Marston Linehan, Tara Hiltke, Feng Chen, Lijun Chen, Jan Lubinski, Chelsea J. Newton, Steven A. Carr, Tatiana Omelchenko, Gilbert S. Omenn, Karsten Krug, Ana I. Robles, Azra Krek, Runyu Hong, Milan G. Chheda, Yize Li, Yan Shi, Lili Blumenberg, Ruiyang Liu, Karin D. Rodland, Hua Sun, Kim Elburn, Jeffrey R. Whiteaker, Christopher J. Ricketts, Gaddy Getz, Daniel W. Chan, Bo Wen, Robert Edwards, Patricia Castro, Yingwei Hu, Pushpa Hariharan, Simina M. Boca, Darlene Tansil, Phillip M. Pierorazio, Yosef E. Maruvka, Sandra Cottingham, James J. Hsieh, Amanda G. Paulovich, Barbara Pruetz, Michael A. Gillette, Yihao Lu, Dmitry Rykunov, Mehdi Mesri, Marc M. Loriaux, Reyka G Jayasinghe, and Suhas Vasaikar

Subjects
Adult, Male, Cell, Computational biology, Biology, Proteomics, Disease-Free Survival, Oxidative Phosphorylation, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Biomarkers, Tumor, Tumor Microenvironment, Humans, Exome, Phosphorylation, Carcinoma, Renal Cell, 030304 developmental biology, Epigenomics, Aged, Proteogenomics, Aged, 80 and over, 0303 health sciences, Tumor microenvironment, Genome, Human, Phosphoproteomics, Middle Aged, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Clear cell renal cell carcinoma, medicine.anatomical_structure, Female, 030217 neurology & neurosurgery, Signal Transduction
Abstract

SUMMARY To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology., Graphical Abstract, In Brief Comprehensive proteogenomic characterization in 103 treatment-naive clear cell renal cell carcinoma patient samples highlights tumor-specific alterations at the proteomic level that are unrevealed by transcriptomic profiling and proposes a revised subtyping scheme based on integrated omics analysis.

Published
2020
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33. Abstract 2412: Development of a gene signature to predict positive or negative sentinel nodes as a prognostic marker in melanoma

Author

Audrey J. Majeske, Timothy J. Geddes, Richard Keidan, and George D. Wilson

Subjects
Cancer Research, Oncology
Abstract

In recent years, sentinel lymph node (SLN) biopsy has been adopted as a less invasive technique to assess the prognostic outcome of melanoma, whereby draining the key lymph nodes for presence of a tumor decreases unnecessary lymph node dissections and reduces the risk of developing lymphedema. However, this technique only has therapeutic value in patients with SLN-positive tumor nodes, which only represents about half of the population diagnosed with melanoma. In a pilot study, we assessed the predictive efficacy of using a commercialized multi-biomarker next-generation sequencing (NGS) assay (Illumina® Comprehensive Cancer Panel) containing selected genes which have been shown to have a prognostic impact in melanoma progression, to determine whether these can identify primary tumors which do not require SLN biopsy. We used laser capture microdissection to capture pathologist-identified areas of tumor from four groups of samples 1) skin lesions from SLN-positive patients, 2) skin lesions from SLN-negative patients, 3) node samples from SLN-positive patients and node samples from SLN-negative patients; some cases of skin lesions and nodes were matched for the same patient. Sequencing identified 14 genes containing variants in >70% of the positive node samples, which were absent in samples with negative nodes. This included EGFR, PDGFR, ATM, PIK3CA, TP53 and ERBB4. Of note, variants in ERBB4 is of interest as it has been shown in the past to be a potential molecular target in the treatment of melanoma. We are currently validating these preliminary findings in a larger cohort of patients (n=31) and will report on the NGS findings of this study and the efficacy of using genetic biomarkers in skin biopsy samples as a potential prognostic marker for early stage melanoma patients who may not require SLN biopsy. Citation Format: Audrey J. Majeske, Timothy J. Geddes, Richard Keidan, George D. Wilson. Development of a gene signature to predict positive or negative sentinel nodes as a prognostic marker in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2412.

Published
2019
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34. Crizotinib Fails to Enhance the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Xenografts

Author

Andrew M, Baschnagel, Sandra, Galoforo, Bryan J, Thibodeau, Samreen, Ahmed, Sonali, Nirmal, Jan, Akervall, and George D, Wilson

Subjects
DNA Copy Number Variations, Pyridines, Blotting, Western, Mice, Nude, Apoptosis, Real-Time Polymerase Chain Reaction, Radiation Tolerance, Immunoenzyme Techniques, Mice, Crizotinib, Tumor Cells, Cultured, Animals, Humans, RNA, Messenger, Phosphorylation, Protein Kinase Inhibitors, Cell Proliferation, Reverse Transcriptase Polymerase Chain Reaction, X-Rays, Proto-Oncogene Proteins c-met, Xenograft Model Antitumor Assays, Head and Neck Neoplasms, Carcinoma, Squamous Cell, Pyrazoles, Female, Signal Transduction
Abstract

Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model.Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity.All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UT-SCC-15 tumors grown as xenografts.MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model.

Published
2015

35. Glucose metabolism gene expression patterns and tumor uptake of ¹⁸F-fluorodeoxyglucose after radiation treatment

Author

George D, Wilson, Bryan J, Thibodeau, Laura E, Fortier, Barbara L, Pruetz, Sandra, Galoforo, Andrew M, Baschnagel, John, Chunta, Ching Yee, Oliver Wong, Di, Yan, Brian, Marples, and Jiayi, Huang

Subjects
Glucose Transporter Type 1, Gene Expression, Mice, Nude, Immunohistochemistry, Tumor Burden, Random Allocation, Glucose, Fluorodeoxyglucose F18, Head and Neck Neoplasms, Cell Line, Tumor, Hexokinase, Positron-Emission Tomography, Carcinoma, Squamous Cell, Animals, Heterografts, Female, RNA, Messenger, Radiopharmaceuticals
Abstract

To investigate whether radiation treatment influences the expression of glucose metabolism genes and compromises the potential use of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool to monitor the early response of head and neck cancer xenografts to radiation therapy (RT).Low passage head and neck squamous cancer cells (UT14) were injected to the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm(3) they were treated with either sham RT or 15 Gy in 1 fraction. At different time points, days 3, 9, and 16 for controls and days 4, 7, 12, 21, 30, and 40 after irradiation, 2 to 3 mice were assessed with dynamic FDG-PET acquisition over 2 hours. Immediately after the FDG-PET the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data.Radiation had no effect on key genes involved in FDG uptake and metabolism but did alter other genes in the HIF1α and glucose transport-related pathways. In contrast to the lack of effect on gene expression, changes in the protein expression patterns of the key genes GLUT1/SLC2A1 and HK2 were observed after radiation treatment. The changes in GLUT1 protein expression showed some correlation with dynamic FDG-PET parameters, such as the kinetic index.(18)F-fluorodeoxyglucose positron emission tomography changes after RT would seem to represent an altered metabolic state and not a direct effect on the key genes regulating FDG uptake and metabolism.

Published
2014

37. Isolation and genomic characterization of stem cells in head and neck cancer

Author

George D, Wilson, Brian, Marples, Sandra, Galoforo, Timothy J, Geddes, Bryan J, Thibodeau, Reidar, Grénman, and Jan, Akervall

Subjects
Paclitaxel, Squamous Cell Carcinoma of Head and Neck, Cell Cycle, Cell Separation, Genomics, Flow Cytometry, Radiation Tolerance, Sensitivity and Specificity, Gene Expression Regulation, Neoplastic, Hyaluronan Receptors, Head and Neck Neoplasms, Carcinoma, Squamous Cell, Neoplastic Stem Cells, Tumor Cells, Cultured, Humans, Cisplatin, Cell Proliferation
Abstract

This study investigated the use of 3 different established cell-sorting strategies to isolate and characterize stem cells from head and neck cancer cell lines.Five low-passage cell lines were subjected to cell sorting based on Hoechst side population, Aldefluor, and CD44 expression. Isolated cell populations were studied for gene expression, radiosensitivity, and chemosensitivity to cisplatin and paclitaxel.Each sorting method identified a different set of genes associated with different gene ontology categories, with mitosis being the only common category. CD44-associated gene changes were almost exclusively associated with cell cycle and in particular mitosis. There were no significant differences in radiosensitivity or cisplatin sensitivity of stem or non-stem cells, but CD44-isolated stem cells were more resistant to paclitaxel.This study suggested that CD44 may be the most promising cell-sorting strategy to isolate and investigate the impact of stem cells in head and neck squamous cell cancer (HNSCC).

Published
2012

38. Flow cytometric DNA analysis of human cancers and cell lines

Author

Sarah A, Krueger and George D, Wilson

Subjects
Cell Nucleus, Tissue Fixation, Ethanol, Staining and Labeling, Cell Line, Tumor, Neoplasms, Animals, Humans, DNA, Reference Standards, Flow Cytometry, Pepsin A
Abstract

Measurement of DNA content was one of the first applications to be developed in the use of flow cytometry and is still used routinely in many experimental and, to a lesser extent, clinical studies. The goal of this technique is to produce a high quality DNA profiles for accurate analysis of DNA content and cell cycle distribution. In this chapter, we describe three DNA measurement methods that satisfy this requirement in different situations. It is widely accepted that the Vindelov method produces the highest quality DNA profiles in nuclei from solid tumours or cell lines. However, in many situations, DNA content is combined with another marker, so we describe a method which produces high quality DNA profiles in intact cells. Third, because the Vindelov technique requires prompt processing of fresh tumours, so we also describe a technique that derives nuclei from ethanol fixed tumours providing the convenience of storage before processing.

Published
2011

39. TMPRSS2/ERG fusion gene expression alters chemo- and radio-responsiveness in cell culture models of androgen independent prostate cancer

Author

Todd A, Swanson, Sarah A, Krueger, Sandra, Galoforo, Bryan J, Thibodeau, Alvaro A, Martinez, George D, Wilson, and Brian, Marples

Subjects
Male, DNA Repair, Oncogene Proteins, Fusion, Paclitaxel, Serine Endopeptidases, Prostatic Neoplasms, Chemoradiotherapy, Adenocarcinoma, Antineoplastic Agents, Phytogenic, Gene Expression Regulation, Neoplastic, Phenotype, Transcriptional Regulator ERG, Cell Line, Tumor, Androgens, Trans-Activators, Humans
Abstract

The androgen regulated transmembrane serine protease (TMPRSS2) and ETS transcription factor (ERG) gene fusion is a strong prognostic factor for disease recurrence following prostatectomy. Expression of TMPRSS2/ETS-related gene (ERG) fusion gene transcripts is linked with tumor proliferation, invasion, and an aggressive phenotype. The aim of this study was to define the effect of TMPRSS2/ERG fusion gene expression on chemo- and radiosensitivity in prostate tumor cell lines.Clonogenic survival of PC3 and DU145 cells stably expressing TMPRSS2/ERG Types III and VI fusion genes was measured after X-irradiation (0-8 Gy) and Paclitaxel. Cell cycle changes and DNA double-strand break induction and repair were assessed. Differential gene expression was measured by microarray analysis. ERG signaling pathway interactions were studied using Ariadne Pathway Studio.Expression of the TMPRSS2/ERG fusions in PC3 cells increased radiation sensitivity and decreased paclitaxel sensitivity. Increased radiosensitivity was associated with persistent DNA breaks 24 hr post-irradiation, down-regulation of genes involved in DNA repair and mitosis and up-regulation of ETV, an ETS transcription factor. However, DU145 Types III and VI demonstrated a different sensitivity phenotype and gene expression changes. Pathway analysis of ERG signaling further illustrated the variation between the PC3 and DU145 cell lines containing TMPRSS2/ERG fusions.The effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio- and chemosensitivity in vivo.

Published
2011

44. Mechanisms of Enhanced Cell Killing at Low Doses: Implications for Radiation Risk

Author

Peter J. Johnston and George D. Wilson

Subjects
DNA repair, business.industry, Cell, Biology, Cell cycle, Cell killing, medicine.anatomical_structure, Apoptosis, Cancer research, medicine, Lethality, Irradiation, Radiosensitivity, Nuclear medicine, business
Abstract

We have shown that cell lethality actually measured after exposure to low-doses of low-LET radiation, is markedly enhanced relative to the cell lethality previously expected by extrapolation of the high-dose cell-killing response. Net cancer risk is a balance between cell transformation and cell kill and such enhanced lethality may more than compensate for transformation at low radiation doses over a least the first 10 cGy of low-LET exposure. This would lead to a non-linear, threshold, dose-risk relationship. Therefore our data imply the possibility that the adverse effects of small radiation doses (

Published
2003
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45. Tumor hypoxia and blood vessel detection: an image analysis technique for simultaneous tumor hypoxia grading and blood vessel detection in tissue sections

Author

Constantinos G, Loukas, George D, Wilson, Borivoj, Vojnovic, and Alf, Linney

Subjects
Microscopy, Fuzzy Logic, Urinary Bladder Neoplasms, Carcinoma, Image Processing, Computer-Assisted, Humans, Endothelium, Vascular, Algorithms, Cell Hypoxia
Abstract

We have developed a multistage image analysis technique for the simultaneous segmentation of blood vessels and hypoxic regions in dual-stained tumor tissue sections. The algorithm, which is integrated in a task-oriented image analysis system developed on-site, initially uses the K-nearest neighbor classification rule in order to label the image pixels. Classification is based on a training set selected from manually drawn regions corresponding to the areas of interest. If the output image contains a significant number of misclassified pixels, the user has the option to apply a series of specific problem-designed routines (texture analysis, fuzzy c-means clustering, and edge detection) in order to improve the final segmentation result. Validation experiments indicate that the algorithm can robustly detect these biological features, even in tissue sections with a very low quality of staining. This approach has also been combined with other image analysis based procedures in order to objectively obtain quantitative measurements of potential clinical interest.

Published
2003

47. Radiation and the cell cycle, revisited.

Author

George D. Wilson

Abstract

The cell cycle has been inextricably linked to the cellular response to radiation for many years. However, it is only in the past decade that the concept of a coordinated DNA damage response integrating damage recognition, cell cycle checkpoints and DNA repair has begun to be elucidated. The ATM protein is emerging as a key orchestrator of the damage response activating a wide variety of effectors involved in cell cycle arrest and DNA repair to elicit a concerted effort to prevent genome instability caused by unwanted changes in DNA sequence. The key proteins involved in cell cycle checkpoints in different phases of the cell cycle, and their interaction, is a fertile and rapidly developing area of research. This review summarizes the current state of knowledge of cellular checkpoints in response to radiation-induced double-strand breaks in mammalian cells and how this impacts on radiosensitivity. [ABSTRACT FROM AUTHOR]

Published
2004

50. Physical Dimensions of Counseling: Perspective for the Helping Professions

Author

George D. Wilson, Carol Dillon, Mark E. Meadows, Chester W. Jenkins, William L. Deaton, and James C. Hilyer

Subjects
Higher education, Life style, business.industry, education, Perspective (graphical), Physical fitness, Self-concept, Mental health, Education, Clinical Psychology, Graduate students, Developmental and Educational Psychology, business, Psychology, Health habits, Clinical psychology
Abstract

Fifteen graduate students in the helping professions registered in a course that teaches helpers to use physical fitness as a counseling medium. The enrolled graduate students were matched with controls in four relevant areas, and both groups were pretested on 7 physiological and 11 psychological variables. The experimental students were given a 10-week treatment of physical fitness training, counseling in health habits, a life-style of well-being, and instruction in how to deliver these kinds of treatments to clients. For eight weeks the students used the skills in working with real clients. The experimental and control groups were posttested on the same variables; and multivariate and univariate analyses revealed significantly positive changes made by the experimental group. This article reports implications for graduate programs in the helping professions.

Published
1980
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