Publications by authors named "Andrew Goodspeed"

16 Publications

  • Page 1 of 1

Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer.

Cancer Res 2021 Feb 1. Epub 2021 Feb 1.

Radiation Oncology, University of Colorado Denver

Stromal fibrosis activates pro-survival and pro-epithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell surface proteins, A disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after RT. RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with EphrinB2 FC-protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after radiation therapy and identifies a targetable pathway to enhance RT efficacy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3892DOI Listing
February 2021

CPT1A Over-Expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer.

Cancers (Basel) 2020 Nov 18;12(11). Epub 2020 Nov 18.

Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Cancers reprogram their metabolism to adapt to environmental changes. In this study, we examined the consequences of altered expression of the mitochondrial enzyme carnitine palmitoyl transferase I (CPT1A) in prostate cancer (PCa) cell models. Using transcriptomic and metabolomic analyses, we compared LNCaP-C4-2 cell lines with depleted (knockdown (KD)) or increased (overexpression (OE)) CPT1A expression. Mitochondrial reactive oxygen species (ROS) were also measured. Transcriptomic analysis identified ER stress, serine biosynthesis and lipid catabolism as significantly upregulated pathways in the OE versus KD cells. On the other hand, androgen response was significantly downregulated in OE cells. These changes associated with increased acyl-carnitines, serine synthesis and glutathione precursors in OE cells. Unexpectedly, OE cells showed increased mitochondrial ROS but when challenged with fatty acids and no androgens, the Superoxide dismutase 2 (SOD2) enzyme increased in the OE cells, suggesting better antioxidant defenses with excess CPT1A expression. Public databases also showed decreased androgen response correlation with increased serine-related metabolism in advanced PCa. Lastly, worse progression free survival was observed with increased lipid catabolism and decreased androgen response. Excess CPT1A is associated with a ROS-mediated stress phenotype that can support PCa disease progression. This study provides a rationale for targeting lipid catabolic pathways for therapy in hormonal cancers.
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http://dx.doi.org/10.3390/cancers12113431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709014PMC
November 2020

KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma.

Oncotarget 2020 Oct 27;11(43):3818-3831. Epub 2020 Oct 27.

Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

Ewing sarcoma is an aggressive malignant neoplasm with high propensity for metastasis and poor clinical outcomes. The EWS/Fli1 oncofusion is the disease driver in > 90% of cases, but presents a difficult therapeutic target. Moreover, EWS/Fli1 plays a complex role in disease progression, with inhibitory effects on critical steps of metastasis. Like many other pediatric cancers, Ewing sarcoma is a disease marked by epigenetic dysregulation. Epigenetic mechanisms present alternative targeting opportunities, but their contributions to Ewing sarcoma metastasis and disease progression remain poorly understood. Here, we show that the epigenetic regulators KDM5A and PHF2 promote growth and metastatic properties in Ewing sarcoma, and, strikingly, activate expression many pro-metastatic genes repressed by EWS/Fli1. These genes include L1CAM, which is associated with adverse outcomes in Ewing sarcoma, and promotes migratory and invasive properties. KDM5A and PHF2 retain their growth promoting effects in more metastatically potent EWS/Fli1 cells, and PHF2 promotes both invasion and L1CAM expression in this cell population. Furthermore, KDM5A and PHF2 each contribute to the increased metastatic potency of EWS/Fli1 cells . Together, these studies identify KDM5A and PHF2 as novel disease-promoting factors, and potential new targets, in Ewing sarcoma, including the more metastatically potent EWS/Fli1 cell population.
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http://dx.doi.org/10.18632/oncotarget.27737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597412PMC
October 2020

Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of -Mutant Breast Cancer.

Cancer Res 2021 Feb 12;81(3):732-746. Epub 2020 Nov 12.

Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Mutations in that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1 macrophages..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854521PMC
February 2021

KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma.

Mol Oncol 2020 10 5;14(10):2471-2486. Epub 2020 Aug 5.

Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. RMS exists as two major disease subtypes, oncofusion-negative RMS (FN-RMS) and oncofusion-positive RMS (FP-RMS). FP-RMS is characterized by recurrent PAX3/7-FOXO1 driver oncofusions and is a biologically and clinically aggressive disease. Recent studies have revealed FP-RMS to have a strong epigenetic basis. Epigenetic mechanisms represent potential new therapeutic vulnerabilities in FP-RMS, but their complex details remain to be defined. We previously identified a new disease-promoting epigenetic axis in RMS, involving the chromatin factor KDM3A and the Ets1 transcription factor. In the present study, we define the KDM3A and Ets1 FP-RMS transcriptomes and show that these interface with the recently characterized PAX3/FOXO1-driven gene expression program. KDM3A and Ets1 positively control numerous known and candidate novel PAX3/FOXO1-induced RMS-promoting genes, including subsets under control of PAX3/FOXO1-associated superenhancers (SE), such as MEST. Interestingly, KDM3A and Ets1 also positively control a number of known and candidate novel FP-RMS-promoting, but not PAX3/FOXO1-dependent, genes. Epistatically, Ets1 is downstream of, and exerts disease-promoting effects similar to, both KDM3A and PAX3/FOXO1. MEST also manifests disease-promoting properties in FP-RMS, and KDM3A and Ets1 each impacts activation of the PAX3/FOXO1-associated MEST SE. Taken together, our studies show that the KDM3A/Ets1 epigenetic axis plays an important role in disease promotion in FP-RMS, and provide insight into potential new ways to target aggressive phenotypes in this disease.
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http://dx.doi.org/10.1002/1878-0261.12769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530783PMC
October 2020

Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis.

Cancer Res 2020 06 27;80(12):2689-2702. Epub 2020 Apr 27.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Metastasis is the major cause of mortality for patients with cancer, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGFβ signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGFC-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGFβ signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer-associated metastasis without significantly altering primary tumor growth. Thus, we have demonstrated for the first time that pharmacologic inhibition of the SIX1/EYA2 complex and associated phenotypes is sufficient to suppress breast cancer metastasis. SIGNIFICANCE: These findings identify and characterize a novel inhibitor of the SIX1/EYA2 complex that reverses EMT phenotypes suppressing breast cancer metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510951PMC
June 2020

Leptomeningeal Metastasis from Adrenocortical Carcinoma: A Case Report.

J Endocr Soc 2020 Mar 12;4(3):bvaa017. Epub 2020 Feb 12.

Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado.

Adrenocortical carcinoma (ACC) is an uncommon endocrine malignancy with limited treatment options. While the overall 5-year survival rate in patients with ACC is 35%, the disease is often rapidly progressive with long-term survival in only 5% of patients. Although tumor stage, grade, and excess hormonal activity predict unfavorable prognosis, additional biomarkers are needed to identify patients with aggressive disease. A 23-year-old woman presented with rapidly progressing signs and symptoms of Cushing's syndrome, with associated abdominal pain and fullness. Evaluation revealed a large left adrenal mass which had developed over 8 months. En bloc surgical resection was performed by an endocrine surgeon, and pathology revealed adrenocortical carcinoma with Ki67 of 60%. Despite adjuvant treatment with mitotane and etoposide-doxorubicin-carboplatin chemotherapy, the patient had rapid disease progression with metastatic spread to liver, lung, bone, brain, and leptomeningies, and she died 11 months after the initial diagnosis. Subsequent analysis of the patient's tumor revealed mutations in and . RNA sequencing was compared against the the Cancer Genome Atlas data set and clustered with the high steroid, proliferative subtype, associated with the worst prognosis. The tumor also demonstrated a low ratio and G0S2 hypermethylation, both predictive of very aggressive ACC. This case represents a subset of ACC characterized by rapid and fatal progression. Clinically available predictors as well as recently reported molecular signatures and biomarkers correlated with this tumor's aggressiveness, suggesting that development and validation of combinations of biomarkers may be useful in guiding personalized approaches to patients with ACC.
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http://dx.doi.org/10.1210/jendso/bvaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053406PMC
March 2020

Leveraging the utility of pharmacogenomics in psychiatry through clinical decision support: a focus group study.

Ann Gen Psychiatry 2019 8;18:13. Epub 2019 Aug 8.

RxRevu, Inc, 2601 Blake Street Suite 450, Denver, CO 80205 USA.

Background: Pharmacogenomics is starting to build momentum in clinical utility, perhaps the most in mental and behavioral healthcare. However, efficient delivery of this information to the point of prescribing remains a significant challenge. Clinical decision support has an opportunity to address this void by integrating pharmacogenomics into the clinician workflow.

Methods: To address the specific needs of mental health clinicians at the point of care, we conducted 3 focus groups with a total of 16 mental health clinicians. Each 1-h focus group was designed to identify the desired clinical decision support features, with a particular interest in pharmacogenomics, and potential negative or unintended consequences of clinical decision support integration at the point of care in a mental healthcare setting. We implemented an iterative design to expand upon knowledge generated in prior focus groups. The results from the guided discussion in the first focus group were used to develop a mental health clinical decision support prototype. This prototype was then presented during the next two focus groups to drive the discussion.

Results: This study has identified main themes related to the desired clinical decision support features of mental health clinicians, the use of pharmacogenomics in practice, and unintended and negative consequences of clinical decision support integration at the point of care. Clinicians desire a more complete picture of the medication history of patients and guidance to choose medications in relation to cost, insurance coverage, and pharmacogenetics interactions. Mental health clinicians agreed that pharmacogenetics is useful and impacts their prescribing decisions when the data are available. Several negative consequences of clinical decision support integration were identified including alert fatigue and frustration using the tool. Several points of contention were related to the integration of the clinical decision support with the electronic health record, including bidirectional flow of information, speed, location within workflow, and potential incompleteness of information.

Conclusions: We have identified general and unique considerations of mental health clinicians with regard to clinical decision support. Clinical decision support that incorporates desired features while avoiding negative and unintended consequences will increase clinician usage and will have the potential to improve the care of patients.
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http://dx.doi.org/10.1186/s12991-019-0237-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688280PMC
August 2019

Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition.

Dev Cell 2019 09 1;50(6):690-703.e6. Epub 2019 Aug 1.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

While autophagy is thought to be an essential process in some cancer cells, it is unknown if or how such cancer cells can circumvent autophagy inhibition. To address this, we developed a CRISPR/Cas9 assay with dynamic live-cell imaging to measure acute effects of knockout (KO) of autophagy genes compared to known essential and non-essential genes. In some cancer cells, autophagy is as essential for cancer cell growth as mRNA transcription or translation or DNA replication. However, even these highly autophagy-dependent cancer cells evolve to circumvent loss of autophagy by upregulating NRF2, which is necessary and sufficient for autophagy-dependent cells to circumvent ATG7 KO and maintain protein homeostasis. Importantly, however, this adaptation increases susceptibly to proteasome inhibitors. These studies identify a common mechanism of acquired resistance to autophagy inhibition and show that selection to avoid tumor cell dependency on autophagy creates new, potentially actionable cancer cell susceptibilities.
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http://dx.doi.org/10.1016/j.devcel.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233142PMC
September 2019

Nanoparticles Containing an Insulin-ChgA Hybrid Peptide Protect from Transfer of Autoimmune Diabetes by Shifting the Balance between Effector T Cells and Regulatory T Cells.

J Immunol 2019 07 20;203(1):48-57. Epub 2019 May 20.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;

CD4 T cells play a critical role in promoting the development of autoimmunity in type 1 diabetes. The diabetogenic CD4 T cell clone BDC-2.5, originally isolated from a NOD mouse, has been widely used to study the contribution of autoreactive CD4 T cells and relevant Ags to autoimmune diabetes. Recent work from our laboratory has shown that the Ag for BDC-2.5 T cells is a hybrid insulin peptide (2.5HIP) consisting of an insulin C-peptide fragment fused to a peptide from chromogranin A (ChgA) and that endogenous 2.5HIP-reactive T cells are major contributors to autoimmune pathology in NOD mice. The objective of this study was to determine if poly(lactide--glycolide) (PLG) nanoparticles (NPs) loaded with the 2.5HIP Ag (2.5HIP-coupled PLG NPs) can tolerize BDC-2.5 T cells. Infusion of 2.5HIP-coupled PLG NPs was found to prevent diabetes in an adoptive transfer model by impairing the ability of BDC-2.5 T cells to produce proinflammatory cytokines through induction of anergy, leading to an increase in the ratio of Foxp3 regulatory T cells to IFN-γ effector T cells. To our knowledge, this work is the first to use a hybrid insulin peptide, or any neoepitope, to re-educate diabetogenic T cells and may have significant implications for the development of an Ag-specific therapy for type 1 diabetes patients.
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http://dx.doi.org/10.4049/jimmunol.1900127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581587PMC
July 2019

A Whole-genome CRISPR Screen Identifies a Role of MSH2 in Cisplatin-mediated Cell Death in Muscle-invasive Bladder Cancer.

Eur Urol 2019 02 7;75(2):242-250. Epub 2018 Nov 7.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address:

Background: The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades.

Objective: To identify genes that influence cisplatin resistance in bladder cancer.

Design, Setting, And Participants: We performed a whole-genome CRISPR screen in a bladder cancer cell line to identify genes that mediate resistance to cisplatin.

Outcome Measurements And Statistical Analysis: Targeted validation was performed in two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset.

Results And Limitations: From the CRISPR screen, we identified MSH2 as the most significantly enriched gene and mismatch repair as the most significantly enriched pathway that promoted resistance to cisplatin. Bladder cancer cells with knockdown of MSH2 showed a reduction in cisplatin-mediated apoptosis. MSH2 loss did not impact the sensitivity to other chemotherapies, including the cisplatin analog oxaliplatin. Bladder tumors with low MSH2 protein levels, quantified using reverse-phase protein array, showed poorer survival when treated with cisplatin- or carboplatin-based therapy; these results require future validation using immunohistochemistry. Additionally, results are retrospective from patients with primarily high-grade tumors; thus, validation in a controlled clinical trial is needed.

Conclusions: We generated in vitro evidence that bladder cancer cell lines depleted of MSH2 are more resistant to cisplatin. We additionally found an association between low MSH2 in bladder tumors and poorer patient survival when treated with platinum-based chemotherapy. If successfully validated prospectively, MSH2 protein level could assist in the selection of patients for chemotherapy.

Patient Summary: We report the first evidence that MSH2 protein level may contribute to chemotherapy resistance observed in muscle-invasive bladder cancer. MSH2 has potential as a biomarker predictive of response to platinum-based therapy.
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http://dx.doi.org/10.1016/j.eururo.2018.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339584PMC
February 2019

A Gene Expression Signature Predicts Bladder Cancer Cell Line Sensitivity to EGFR Inhibition.

Bladder Cancer 2018 Jul 30;4(3):269-282. Epub 2018 Jul 30.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Background: Bladder cancer remains a cancer type in need of novel and alternative therapies. While multiple inhibitors of EGFR have been evaluated for efficacy in bladder cancer, the results have largely been disappointing with few patients responding to these therapies. Yet, there is a subset of patients that positively responds to EGFR inhibition with tumor shrinkage, indicating it is an effective treatment for a targeted set of bladder tumors.

Objective: To derive a gene expression signature capable of predicting the response to EGFR inhibition in bladder cancer cell lines.

Methods: he response to cetuximab for 68 colorectal cancer patients was used as training data to generate a gene expression signature. We applied this signature to bladder cancer cell lines and predictions were compared to the responses to seven EGFR inhibitors.

Results: A novel 67-gene signature derived from colorectal cancer was able to significantly identify bladder cancer cell lines by their response to several EGFR inhibitors.

Conclusions: The 67-gene signature can determine bladder cancer cell line sensitivity to EGFR inhibition. This work demonstrates a preclinical strategy to identify bladder cancer cell lines for EGFR-targeted therapy.
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http://dx.doi.org/10.3233/BLC-170161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087449PMC
July 2018

GSEA-InContext: identifying novel and common patterns in expression experiments.

Bioinformatics 2018 07;34(13):i555-i564

Computational Bioscience Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Motivation: Gene Set Enrichment Analysis (GSEA) is routinely used to analyze and interpret coordinate pathway-level changes in transcriptomics experiments. For an experiment where less than seven samples per condition are compared, GSEA employs a competitive null hypothesis to test significance. A gene set enrichment score is tested against a null distribution of enrichment scores generated from permuted gene sets, where genes are randomly selected from the input experiment. Looking across a variety of biological conditions, however, genes are not randomly distributed with many showing consistent patterns of up- or down-regulation. As a result, common patterns of positively and negatively enriched gene sets are observed across experiments. Placing a single experiment into the context of a relevant set of background experiments allows us to identify both the common and experiment-specific patterns of gene set enrichment.

Results: We compiled a compendium of 442 small molecule transcriptomic experiments and used GSEA to characterize common patterns of positively and negatively enriched gene sets. To identify experiment-specific gene set enrichment, we developed the GSEA-InContext method that accounts for gene expression patterns within a background set of experiments to identify statistically significantly enriched gene sets. We evaluated GSEA-InContext on experiments using small molecules with known targets to show that it successfully prioritizes gene sets that are specific to each experiment, thus providing valuable insights that complement standard GSEA analysis.

Availability And Implementation: GSEA-InContext implemented in Python, Supplementary results and the background expression compendium are available at: https://github.com/CostelloLab/GSEA-InContext.
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http://dx.doi.org/10.1093/bioinformatics/bty271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022535PMC
July 2018

GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis.

Cancer Res 2016 09 16;76(17):5175-85. Epub 2016 Jun 16.

Department of Pharmacology, University of Colorado, Denver, Colorado. Department of Surgery (Urology), University of Colorado, Denver, Colorado. University of Colorado Comprehensive Cancer Center, Denver, Colorado.

In principle, the inhibition of candidate gain-of-function genes defined through genomic analyses of large patient cohorts offers an attractive therapeutic strategy. In this study, we focused on changes in expression of CD24, a well-validated clinical biomarker of poor prognosis and a driver of tumor growth and metastasis, as a benchmark to assess functional relevance. Through this approach, we identified GON4L as a regulator of CD24 from screening a pooled shRNA library of 176 candidate gain-of-function genes. GON4L depletion reduced CD24 expression in human bladder cancer cells and blocked cell proliferation in vitro and tumor xenograft growth in vivo Mechanistically, GON4L interacted with transcription factor YY1, promoting its association with the androgen receptor to drive CD24 expression and cell growth. In clinical bladder cancer specimens, expression of GON4L, YY1, and CD24 was elevated compared with normal bladder urothelium. This pathway is biologically relevant in other cancer types as well, where CD24 and the androgen receptor are clinically prognostic, given that silencing of GON4L and YY1 suppressed CD24 expression and growth of human lung, prostate, and breast cancer cells. Overall, our results define GON4L as a novel driver of cancer growth, offering new biomarker and therapeutic opportunities. Cancer Res; 76(17); 5175-85. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010501PMC
September 2016

Tumor-Derived Cell Lines as Molecular Models of Cancer Pharmacogenomics.

Mol Cancer Res 2016 Jan 6;14(1):3-13. Epub 2015 Aug 6.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Compared with normal cells, tumor cells have undergone an array of genetic and epigenetic alterations. Often, these changes underlie cancer development, progression, and drug resistance, so the utility of model systems rests on their ability to recapitulate the genomic aberrations observed in primary tumors. Tumor-derived cell lines have long been used to study the underlying biologic processes in cancer, as well as screening platforms for discovering and evaluating the efficacy of anticancer therapeutics. Multiple -omic measurements across more than a thousand cancer cell lines have been produced following advances in high-throughput technologies and multigroup collaborative projects. These data complement the large, international cancer genomic sequencing efforts to characterize patient tumors, such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). Given the scope and scale of data that have been generated, researchers are now in a position to evaluate the similarities and differences that exist in genomic features between cell lines and patient samples. As pharmacogenomics models, cell lines offer the advantages of being easily grown, relatively inexpensive, and amenable to high-throughput testing of therapeutic agents. Data generated from cell lines can then be used to link cellular drug response to genomic features, where the ultimate goal is to build predictive signatures of patient outcome. This review highlights the recent work that has compared -omic profiles of cell lines with primary tumors, and discusses the advantages and disadvantages of cancer cell lines as pharmacogenomic models of anticancer therapies.
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http://dx.doi.org/10.1158/1541-7786.MCR-15-0189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828339PMC
January 2016

Analyzing the role of receptor internalization in the regulation of melanin-concentrating hormone signaling.

Int J Endocrinol 2013 17;2013:143052. Epub 2013 Nov 17.

Department of Biology, 217 Lennon Hall, The College at Brockport, State University of New York, 350 New Campus Drive, Brockport, NY 14420, USA.

The regulation of appetite is complex, though our understanding of the process is improving. The potential role for the melanin-concentrating hormone (MCH) signaling pathway in the treatment of obesity is being explored by many. It was hypothesized that internalization of MCH receptors would act to potently desensitize cells to MCH. Despite potent desensitization of ERK signaling by MCH in BHK-570 cells, we were unable to observe MCH-mediated internalization of MCH receptor 1 (MCHR1) by fluorescence microscopy. A more quantitative approach using a cell-based ELISA indicated only 15% of receptors internalized, which is much lower than that reported in the literature. When β-arrestins were overexpressed in our system, removal of receptors from the cell surface was facilitated and signaling to a leptin promoter was diminished, suggesting that internalization of MCHR1 is sensitive to cellular β-arrestin levels. A dominant-negative GRK construct completely inhibited loss of receptors from the cell surface in response to MCH, suggesting that the internalization observed is phosphorylation-dependent. Since desensitization of MCH-mediated ERK signaling did not correlate with significant loss of MCHR1 from the cell surface, we hypothesize that in this model system regulation of MCH signaling may be the result of segregation of receptors from signaling components at the plasma membrane.
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http://dx.doi.org/10.1155/2013/143052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855962PMC
December 2013