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2017

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Articles 1 - 30 of 191

Full-Text Articles in Cancer Biology

Nuclear Spindles Pave The Way To Metastasis, Patrick J. Hensley, Natasha Kyprianou Dec 2017

Nuclear Spindles Pave The Way To Metastasis, Patrick J. Hensley, Natasha Kyprianou

Urology Faculty Publications

No abstract provided.


Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

University of Massachusetts Medical School Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Expression Of Wnt-Signaling Pathway Genes And Their Associations With Mirnas In Colorectal Cancer, Martha L. Slattery, Lila E. Mullany, Lori C. Sakoda, Wade S. Samowitz, Roger K. Wolff, John R. Stevens, Jennifer S. Herrick Dec 2017

Expression Of Wnt-Signaling Pathway Genes And Their Associations With Mirnas In Colorectal Cancer, Martha L. Slattery, Lila E. Mullany, Lori C. Sakoda, Wade S. Samowitz, Roger K. Wolff, John R. Stevens, Jennifer S. Herrick

Mathematics and Statistics Faculty Publications

The Wnt-signaling pathway functions in regulating cell growth and thus is involved in the carcinogenic process of several cancers, including colorectal cancer. We tested the hypothesis that multiple genes in this signaling pathway are dysregulated and that miRNAs are associated with these dysregulated genes. We used data from 217 colorectal cancer (CRC) cases to evaluate differences in Wnt-signaling pathway gene expression between paired CRC and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most strongly ...


Unseen Science: Modern Discoveries Too Far Away Or Tiny For Human Eyes, Lucy Huang Dec 2017

Unseen Science: Modern Discoveries Too Far Away Or Tiny For Human Eyes, Lucy Huang

Capstones

As science has progressed, scientists have realized that evidence goes beyond the realms of physical sight. Whether it is too small or difficult to find, scientists have developed different ways to get around this problem. We see this in cancer genomics and in extrasolar planetary research. Scientists use what they know and what they measure to validate their work.

https://lucy-huang-9tge.squarespace.com/


The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv Dec 2017

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity ...


Comparative Molecular Characterization Of Typical And Exceptional Responders In Glioblastoma, Kristin Wipfler Dec 2017

Comparative Molecular Characterization Of Typical And Exceptional Responders In Glioblastoma, Kristin Wipfler

Theses & Dissertations

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a small number of patients survive far beyond the median survival time. Investigation of these “exceptional responders” has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of copy number, methylation, gene expression, miRNA expression, and protein expression data sets from The Cancer ...


Identifying The Role Of Janus Kinase 1 In Mammary Gland Development And Breast Cancer, Barbara Swenson Dec 2017

Identifying The Role Of Janus Kinase 1 In Mammary Gland Development And Breast Cancer, Barbara Swenson

Theses & Dissertations

The development of the postnatal mammary gland is tightly controlled by peptide hormones and cytokines. The signaling of these extracellular ligands through their corresponding receptors rely on Janus Kinases (JAKs) that activate downstream Signal Transducers and Activators of Transcription (STATs). The JAK/STAT signaling pathway is crucial for processes such as growth, proliferation, and cell survival of the epithelial tissue, but also for the breakdown and remodeling of the mammary gland via IL-6 class inflammatory cytokines (e.g. LIF and OSM). JAK1 and JAK2, which are expressed in the mammary gland, are thought to have redundant functions. However, our previous ...


Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego Dec 2017

Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancers with a 5-year survival rate of only 8.2%. This is because PDAC is diagnosed in its advanced stages and is characterized by radio and chemotherapy resistance. Aggressiveness of PDAC tumors is attributed to its high metabolic phenotype, which is characterized by increased glycolysis rate and lactate secretion, while oxidative metabolism is reduced. These metabolic features are required to fulfill the biosynthetic demands of proliferating PDAC cells. However, this increase in metabolic activity results in acidification of the extracellular space because the dense fibrotic stroma of PDAC tumors ...


Metabolic Dysregulation And Cancer Mortality In A National Cohort Of Blacks And Whites, Tomi Akinyemiju, Justin Xavier Moore, Suzanne Judd, Susan Lakoski, Michael Goodman, Monika M. Safford, Maria Pisu Dec 2017

Metabolic Dysregulation And Cancer Mortality In A National Cohort Of Blacks And Whites, Tomi Akinyemiju, Justin Xavier Moore, Suzanne Judd, Susan Lakoski, Michael Goodman, Monika M. Safford, Maria Pisu

Epidemiology Faculty Publications

Background: We examined the association between metabolic dysregulation and cancer mortality in a prospective cohort of Black and White adults.

Methods: A total of 25,038 Black and White adults were included in the analysis. Metabolic dysregulation was defined in two ways: 1) using the joint harmonized criteria for metabolic syndrome (MetS) and 2) based on factor analysis of 15 variables characterizing metabolic dysregulation. We estimated hazards ratios (HRs) and 95% confidence intervals (CIs) for the association of MetS and metabolic dysregulation with cancer mortality during follow-up using Cox proportional hazards models.

Results: About 46% of Black and 39% of ...


Runx1 Control Of Mammary Epithelial And Breast Cancer Cell Phenotypes, Deli Hong Dec 2017

Runx1 Control Of Mammary Epithelial And Breast Cancer Cell Phenotypes, Deli Hong

GSBS Dissertations and Theses

Breast cancer remains the most common malignant disease in women worldwide. Despite the advantages of early detection and improved treatments, studies into the mechanisms that initiate and drive breast cancer progression are still required. Recent studies have identified RUNX1, which is an essential transcription factor for hematopoiesis, is one of the most frequently mutated genes in breast cancer patients. However, the role of RUNX1 in the mammary gland is understudied.

In this dissertation, we examined the role of RUNX1 in both normal mammary epithelial and breast cancer cells. Our in vitro studies demonstrated that RUNX1 inhibits epithelial to mesenchymal transition ...


Metformin And Temozolomide, A Synergic Option To Overcome Resistance In Glioblastoma Multiforme Models, Silvia Valtorta, Alessia Lo. Dico, Isabella Raccagni, Daniela Gaglio, Sara Belloli, Letterio S. Politi, Cristina Martelli, Cecilia Diceglie, Marcella Bonanomi, Giulia Ercoli, Valentina Vaira, Luisa Ottobrini, Rosa Maria Moresco Dec 2017

Metformin And Temozolomide, A Synergic Option To Overcome Resistance In Glioblastoma Multiforme Models, Silvia Valtorta, Alessia Lo. Dico, Isabella Raccagni, Daniela Gaglio, Sara Belloli, Letterio S. Politi, Cristina Martelli, Cecilia Diceglie, Marcella Bonanomi, Giulia Ercoli, Valentina Vaira, Luisa Ottobrini, Rosa Maria Moresco

Radiology Publications and Presentations

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor survival. Cytoreduction in association with radiotherapy and temozolomide (TMZ) is the standard therapy, but response is heterogeneous and life expectancy is limited. The combined use of chemotherapeutic agents with drugs targeting cell metabolism is becoming an interesting therapeutic option for cancer treatment. Here, we found that metformin (MET) enhances TMZ effect on TMZ-sensitive cell line (U251) and overcomes TMZ-resistance in T98G GBM cell line. In particular, combined-treatment modulated apoptosis by increasing Bax/Bcl-2 ratio, and reduced Reactive Oxygen Species (ROS) production. We also observed that MET associated with ...


Melk Promotes Melanoma Growth By Stimulating The Nf-Kappab Pathway, Radoslav Janostiak, Navin Rauniyar, Tukiet T. Lam, Jianhong Ou, Lihua Julie Zhu, Michael R. Green, Narendra Wajapeyee Dec 2017

Melk Promotes Melanoma Growth By Stimulating The Nf-Kappab Pathway, Radoslav Janostiak, Navin Rauniyar, Tukiet T. Lam, Jianhong Ou, Lihua Julie Zhu, Michael R. Green, Narendra Wajapeyee

Open Access Articles

Melanoma accounts for more than 80% of skin cancer-related deaths, and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAPK pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition. Of these proteins, 139 were previously reported as substrates of ...


The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio Dec 2017

The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio

UMass Metabolic Network Publications

Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an ...


Characterization Of Notch1 And Pi3k-Pten-Akt/Mtor Pathway Interaction In Head And Neck Squamous Cell Carcinoma, Kyriante' Henry Dec 2017

Characterization Of Notch1 And Pi3k-Pten-Akt/Mtor Pathway Interaction In Head And Neck Squamous Cell Carcinoma, Kyriante' Henry

UT GSBS Dissertations and Theses (Open Access)

Head and neck squamous cell carcinoma (HNSCC) affects various mucosal sites of the upper aerodigestive tract, including the nasal and oral cavities, the nasopharynx, and the oropharynx. More than five hundred thousand new cases of HNSCC occurred in 2011 alone, with 50,000 reported cases in the United States. This trend made HNSCC the seventh most common non-skin cancer worldwide (Ferlay et al., 2015). Although significant epidemiological and pathological advancements have been made, survival rates have not improved much over the last 40 years, leaving a mortality rate that remains at approximately 50%. An unbiased drug screen demonstrated that HNSCC ...


Comparative Oncogenomics Identifies Novel Regulators And Clinical Relevance Of Neural Crest Identities In Melanoma, Arvind M. Venkatesan Dec 2017

Comparative Oncogenomics Identifies Novel Regulators And Clinical Relevance Of Neural Crest Identities In Melanoma, Arvind M. Venkatesan

GSBS Dissertations and Theses

Cancers often resurrect embryonic molecular programs to promote disease progression. In melanomas, which are tumors of the neural crest (NC) lineage, a molecular signature of the embryonic NC is often reactivated. These NC factors have been implicated in promoting pro-tumorigenic features like proliferation, migration and therapy resistance. However, the molecular mechanisms that establish and maintain NC identities in melanomas are largely unknown. Additionally, whether the presence of a NC identity has any clinical relevance for patient melanomas is also unclear. Here, using comparative genomic approaches, I have a) identified a novel role for GDF6-activated BMP signaling in reawakening a NC ...


Ecog-Acrin (E4805) Randomized Phase Ii Study To Determine The Effect Of 2 Different Doses Of Aflibercept In Patients With Metastatic Renal Cell Carcinoma, Roberto Pili, Opeyemi Jegede, Michael A. Carducci, Judith Manola, David L. Groteluschen, Leonard L. Appleman, Glenn Liu, James C. Shanks, Shaker R. Dakhil, Janice Dutcher, Robert S. Dipaola Dec 2017

Ecog-Acrin (E4805) Randomized Phase Ii Study To Determine The Effect Of 2 Different Doses Of Aflibercept In Patients With Metastatic Renal Cell Carcinoma, Roberto Pili, Opeyemi Jegede, Michael A. Carducci, Judith Manola, David L. Groteluschen, Leonard L. Appleman, Glenn Liu, James C. Shanks, Shaker R. Dakhil, Janice Dutcher, Robert S. Dipaola

Internal Medicine Faculty Publications

Background—Aflibercept is a recombinantly-produced fusion protein that has potent anti-VEGF activity. We tested whether aflibercept has clinical activity in clear cell renal cell carcinoma (ccRCC). The recommended Phase 2 dose was 4 mg/kg but several patients treated at 1 mg/kg demonstrated prolonged progression-free survival (PFS). We therefore tested both doses in a parallel group randomized trial.

Methods—Eligible patients (pts) had histologically confirmed advanced or metastatic ccRCC and previous treatments including prior exposure to a VEGF RTKI. Patients received aflibercept (either 1 mg/kg or 4 mg/kg) day 1 of a 14-day cycle until progression. Patients ...


Computational Investigation Of Homologous Recombination Dna Repair Deficiency In Sporadic Breast Cancer, Yue Wang, Matthew H. Ung, Sharon B. Cantor, Chao Cheng Nov 2017

Computational Investigation Of Homologous Recombination Dna Repair Deficiency In Sporadic Breast Cancer, Yue Wang, Matthew H. Ung, Sharon B. Cantor, Chao Cheng

Open Access Articles

BRCAness has important implications in the management and treatment of patients with breast and ovarian cancer. In this study, we propose a computational framework to measure the BRCAness of breast and ovarian tumor samples based on their gene expression profiles. We define a characteristic profile for BRCAness by comparing gene expression differences between BRCA1/2 mutant familial tumors and sporadic breast cancer tumors while adjusting for relevant clinical factors. With this BRCAness profile, our framework calculates sample-specific BRCA scores, which indicates homologous recombination (HR)-mediated DNA repair pathway activity of samples. We found that in sporadic breast cancer high BRCAness ...


Bivalent Epigenetic Control Of Oncofetal Gene Expression In Cancer, Sayyed K. Zaidi, Seth E. Frietze, Jonathan A. Gordon, Jessica L. Heath, Terri Messier, Deli Hong, Joseph R. Boyd, Mingu Kang, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein Nov 2017

Bivalent Epigenetic Control Of Oncofetal Gene Expression In Cancer, Sayyed K. Zaidi, Seth E. Frietze, Jonathan A. Gordon, Jessica L. Heath, Terri Messier, Deli Hong, Joseph R. Boyd, Mingu Kang, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein

UMass Metabolic Network Publications

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency ...


Integrative Microrna And Mrna Deep-Sequencing Expression Profiling In Endemic Burkitt Lymphoma, Cliff I. Oduor, Yasin Kaymaz, Kiprotich Chelimo, Juliana A. Otieno, John Michael Ong'echa, Ann M. Moormann, Jeffrey A. Bailey Nov 2017

Integrative Microrna And Mrna Deep-Sequencing Expression Profiling In Endemic Burkitt Lymphoma, Cliff I. Oduor, Yasin Kaymaz, Kiprotich Chelimo, Juliana A. Otieno, John Michael Ong'echa, Ann M. Moormann, Jeffrey A. Bailey

UMass Center for Clinical and Translational Science Supported Publications

BACKGROUND: Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells.

METHODS: Using more sensitive ...


Identification Of Kit As A Suppressor Of Brafv600e-Mutant Melanoma, James V. Neiswender Nov 2017

Identification Of Kit As A Suppressor Of Brafv600e-Mutant Melanoma, James V. Neiswender

GSBS Dissertations and Theses

Genetic changes acquired in the pigment producing cells of the skin, called melanocytes, can lead to formation of the deadly cancer melanoma. Mutations or amplifications leading to the activation of the RAS/MAPK pathway occur in more than 90% of melanomas. Melanocyte development and survival requires the stimulation of this pathway by the receptor tyrosine kinase (RTK) KIT. In ~2% of melanomas, oncogenic KIT mutations drive tumor formation; however, the majority of melanomas lose wild-type KIT expression, suggesting that KIT could suppress melanoma formation. In human melanoma patients of The Cancer Genome Atlas (TCGA), we found an association between BRAF ...


Intracellular Signaling And Trafficking In Cancer: Role Of Rab5-Gtpase In Migration And Invasion Of Breast Cells, Nicole Porther Nov 2017

Intracellular Signaling And Trafficking In Cancer: Role Of Rab5-Gtpase In Migration And Invasion Of Breast Cells, Nicole Porther

Nicole Porther

Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. Steroid hormones, such as estrogen, and growth factors, which include insulin growth factor I/II (IGF-1/IGF-2) therapy has been associated with most if not all of the features of metastasis. It has been determined that IGF-1 increases cell survival of cancer cells and potentiate the effect of E2 and other ligand growth factors on breast cancer cells. However not much information is available that comprehensively expounds on the roles of insulin growth factor receptor (IGFR) and Rab GTPases may play in breast cancer. The latter, Rab GTPases ...


The Role Of Talin2 In Breast Cancer Tumorigenesis And Metastasis, Liqing Li, Xiang Li, Lei Qi, Piotr G. Rychahou, Naser Jafari, Cai Huang Nov 2017

The Role Of Talin2 In Breast Cancer Tumorigenesis And Metastasis, Liqing Li, Xiang Li, Lei Qi, Piotr G. Rychahou, Naser Jafari, Cai Huang

Markey Cancer Center Faculty Publications

Recent studies show that talin2 has a higher affinity to β-integrin tails and is indispensable for traction force generation and cell invasion. However, its roles in cell migration, cancer cell metastasis and tumorigenesis remain to be determined. Here, we used MDA-MB-231 human breast cancer cells as a model to define the roles of talin2 in cell migration, invasion, metastasis and tumorigenesis. We show here that talin2 knockdown (KD) inhibited cell migration and focal adhesion dynamics, a key step in cell migration, and that talin2 knockout (KO) inhibited cell invasion and traction force generation, the latter is crucial for cell invasion ...


Mtor Kinase Inhibition Effectively Decreases Progression Of A Subset Of Neuroendocrine Tumors That Progress On Rapalog Therapy And Delays Cardiac Impairment, Melissa A. Orr-Asman, Zhengtao Chu, Min Jiang, Mariah Worley, Kathleen Lesance, Sheryl E. Koch, Vinicius S. Carreira, Hanan M. Dahche, David R. Plas, Kakajan Komurov, Xiaoyang Qi, Carol A. Mercer, Lowell B. Anthony, Jack Rubinstein, Hala E. Thomas Nov 2017

Mtor Kinase Inhibition Effectively Decreases Progression Of A Subset Of Neuroendocrine Tumors That Progress On Rapalog Therapy And Delays Cardiac Impairment, Melissa A. Orr-Asman, Zhengtao Chu, Min Jiang, Mariah Worley, Kathleen Lesance, Sheryl E. Koch, Vinicius S. Carreira, Hanan M. Dahche, David R. Plas, Kakajan Komurov, Xiaoyang Qi, Carol A. Mercer, Lowell B. Anthony, Jack Rubinstein, Hala E. Thomas

Internal Medicine Faculty Publications

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice ...


Tox Regulates Growth, Dna Repair, And Genomic Instability In T-Cell Acute Lymphoblastic Leukemia, Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S. Blackburn, Brian J. Abraham, Yuka Namiki, Marc Mansour, Nouran S. Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon De Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B. Silverman, Ruslan I. Sadreyev, John M. Asara, Marjorie A. Oettinger, Wilhelm Haas, A. Thomas Look, Richard A. Young, Raul Mostoslavsky, Graham Dellaire, David M. Langenau Nov 2017

Tox Regulates Growth, Dna Repair, And Genomic Instability In T-Cell Acute Lymphoblastic Leukemia, Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S. Blackburn, Brian J. Abraham, Yuka Namiki, Marc Mansour, Nouran S. Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon De Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B. Silverman, Ruslan I. Sadreyev, John M. Asara, Marjorie A. Oettinger, Wilhelm Haas, A. Thomas Look, Richard A. Young, Raul Mostoslavsky, Graham Dellaire, David M. Langenau

Molecular and Cellular Biochemistry Faculty Publications

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining ...


Development Of Halofluorochromic Polymer Nanoassemblies For The Potential Detection Of Liver Metastatic Colorectal Cancer Tumors Using Experimental And Computational Approaches, Derek Alexander Reichel, Louis T. Curtis, Elizabeth Ehlman, B. Mark Evers, Piotr G. Rychahou, Hermann B. Frieboes, Younsoo Bae Nov 2017

Development Of Halofluorochromic Polymer Nanoassemblies For The Potential Detection Of Liver Metastatic Colorectal Cancer Tumors Using Experimental And Computational Approaches, Derek Alexander Reichel, Louis T. Curtis, Elizabeth Ehlman, B. Mark Evers, Piotr G. Rychahou, Hermann B. Frieboes, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Purpose—To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes.

Methods—We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm.

Results—Dye-conjugated PNAs showed ...


Actionable Gene-Based Classification Toward Precision Medicine In Gastric Cancer, Hiroshi Ichikawa, Stephen Lyle, Toshifumi Wakai Oct 2017

Actionable Gene-Based Classification Toward Precision Medicine In Gastric Cancer, Hiroshi Ichikawa, Stephen Lyle, Toshifumi Wakai

Open Access Articles

BACKGROUND: Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.

METHODS: A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV ...


Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie Oct 2017

Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie

Molecular and Cellular Biochemistry Faculty Publications

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard ...


Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds Oct 2017

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative ...


Role Of High Molecular Weight Hyaluronan In Ultraviolet B Light-Induced Transformation, Katelyn Cousteils Oct 2017

Role Of High Molecular Weight Hyaluronan In Ultraviolet B Light-Induced Transformation, Katelyn Cousteils

Electronic Thesis and Dissertation Repository

Keratinocyte carcinomas (KCs) are the most common cancers globally. Ultraviolet light is the key risk factor for these cancers but sunscreen has proven ineffective in their prevention, indicating a need for new prophylactic agents. Chronic elevation of high molecular weight (HMW) tissue hyaluronan (HA) in skin is linked to tumor resistance in the naked mole rat. To directly assess the role of this polysaccharide in resistance to keratinocyte tumors, a HMW HA phosphatidylethanolamine (HA-PE) formulation that penetrates skin and accumulates as coats around keratinocytes was prepared. The tumor resistance properties of the HA-PE formulation were tested in a mouse model ...


Glycolytic Reprogramming Through Pck2 Regulates Tumor Initiation Of Prostate Cancer Cells, Jiangsha Zhao, Jieran Li, Teresa W.M. Fan, Steven X. Hou Oct 2017

Glycolytic Reprogramming Through Pck2 Regulates Tumor Initiation Of Prostate Cancer Cells, Jiangsha Zhao, Jieran Li, Teresa W.M. Fan, Steven X. Hou

Toxicology and Cancer Biology Faculty Publications

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein ...