Archive for the ‘Seminars Videos’ Category

Geoffrey West, Santa Fe Institute ‘Towards a Quantitative, Predictive Theory of Tumor Growth, Metabolic Rate and Vascular Structure’

Wednesday, January 4th, 2012

Speaker: Geoffrey West, PhD. is a theoretical physicist whose primary interests have been in fundamental questions in physics, especially those concerning the elementary particles, their interactions and cosmological implications. West served as SFI President from July 2005 through July 2009. Prior to joining the Santa Fe Institute as a Distinguished Professor in 2003, he was the leader, and founder, of the high energy physics group at Los Alamos National Laboratory, where he is one of only approximately ten Senior Fellows. His long-term fascination in general scaling phenomena evolved into a highly productive collaboration on the origin of universal scaling laws that pervade biology from the molecular genomic scale up through mitochondria and cells to whole organisms and ecosystems. This led to the development of realistic quantitative models for the structural and functional design of organisms based on underlying universal principles. This work, begun at the Institute, has received much attention in both the scientific and popular press, and provides a framework for quantitative understanding of problems ranging from fundamental issues in biology (such as cell size, growth, metabolic rate, DNA nucleotide substitution rates, and the structure and dynamics of ecosystems) to questions at the forefront of medical research (such as aging, sleep, and cancer). Among his current interests is the extension of these ideas to understand quantitatively the structure and dynamics of social organizations, such as cities and corporations, including the relationships between economies of scale, growth, innovation and wealth creation and their implications for long-term survivability and sustainability.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: January 12, 2012 12:00 p.m.

Title: Towards a Quantitative, Predictive Theory of Tumor Growth, Metabolic Rate and Vascular Structure

Abstract: A conceptual framework successfully developed for quantitatively understanding and predicting many physiological and dynamical properties of mammals and plants, including metabolic rates, ontogenetic growth trajectories and vascular structure, is extended to tumors. The theory presumes that life at all scales from intra- to multi-cellular levels is sustained by space-filling, fractal-like, hierarchical branching networks whose “universal” geometric and dynamical properties provide a mathematical framework that captures the essential features of these diverse systems. When applied to tumors (and their interface with host tissue) the theory yields extensive quantitative predictions for many of their properties, including growth rates, metabolic rates, degree of necrosis, blood flow rates, capillary density and vessel sizes, in good agreement with data. In addition, it shows how these properties depend on both tumor and host size thereby explaining why similar tumors grow systematically slower and occur less frequently in larger animals, shedding light on Peto’s paradox. The role of damage (and consequent entropy production) due to dissipative forces in host networks as a generator of tumors and its relationship to aging, mortality and sleep will be explored. Possible implications for potential therapeutic strategies will be discussed.

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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William Muller – How Endothelial Cells Regulate Leukocyte Transmigration: Application to Cancer Metastasis

Thursday, November 3rd, 2011

Speaker: William Muller, MD, PhD. received his A.B. degree summa cum laude from Harvard University in 1975. He earned his PhD degree from The Rockefeller University in 1981 under the mentorship of Dr. Ralph Steinman and the late Dr. Zanvil Cohn. He received his MD degree in 1982 from Cornell University Medical College as part of the combined MD/PhD program. In 2007 he was recruited to Northwestern University Feinberg School of Medicine as the Magerstadt Professor and Chairman of the Department of Pathology. Dr. Muller’s research focuses on the cellular and molecular basis of the inflammation, and in particular the interactions of leukocytes and endothelial cells in the inflammatory response. Dr. Muller’s research has been well funded by the National Institutes of Health, the American Heart Association, and several biotech companies. He is the recipient of the prestigious MERIT Award from the NIH. He is one of the Editors of The Journal of Experimental Medicine and Annual Reviews of Pathology: Mechanisms of Disease and serves on the editorial boards of several other journals. He has served in many official capacities over the years for the American Society for Investigative Pathology as well as for the North American Vascular Biology Organization (NAVBO) and was elected President of NAVBO in 2004. He was elected a Fellow of the AAAS in 2010.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: November 3rd, 2011 12:00 p.m.

Title: How Endothelial Cells Regulate Leukocyte Transmigration: Application to Cancer Metastasis

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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Thai Tran – Discovery of Prolactin Signaling Pathway in Breast Cancer

Monday, October 10th, 2011

Speaker: Thai Tran, PhD. received his Ph.D. in molecular biology from Purdue University and was trained a as a postdoctoral fellow with Dr. Hallgeir Rui at the Kimmel Cancer Center, Thomas Jefferson University. Dr. Tran has background in molecular and cellular biology of cancer. His research focus is to investigate the molecular functions that govern cancer cell development and progression. Specifically, his research has centered on identifying molecular biomarkers in breast, pancreatic and esophagus cancers using the combined approaches of high throughput immunohistochemistry, molecular and cellular technologies. More recently, he has focused more on dissecting intratumoral heterogeneity at the single-cell level by analyzing gene expression profiles of individual cells freshly isolated from true human clinical samples. The primary goal of this study is to identify minute populations of cells that potentially play major roles in cancer progression and metastasis.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: October 20th, 2011 12:00 p.m.

Title: Discovery of Prolactin Signaling Pathway in Breast Cancer

Abstract: Breast cancer is the second leading cause of deaths among women. In the United States, an estimated 230,480 are diagnosed with breast cancer each year and, of these, 39,520 are expected to die from the disease. This devastating consequence is partly due our inability to detect and provide treatments while the tumor is localized to the breast. As a result, numerous efforts have been made to identify early breast cancer biomarkers. In my talk I will discuss the implications of a number of potential breast cancer biomarkers specifically focusing on the functions of prolactin and its downstream target, Stat5. Unraveling the details of this new mechanism illustrates the complexity of signaling pathways and the formidable challenge of designing chemical intervention.

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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William M. Grady – The Role of Epigenetic Alterations in Colon Cancer

Monday, October 10th, 2011

Speaker: William M. Grady, MD, is a physician-scientist at the Fred Hutchinson Cancer Research Center and the University of Washington Medical School, Seattle, WA. He is the Roger C. Haggitt Professor of Medicine and section Chief of the Gastroenterology Division at the University of Washington Medical School. He is also a full member of the Clinical Research Division of the Fred Hutchinson Cancer Research Center. In addition to being the PI of a translational research program in GI oncology, he is a practicing gastroenterologist and is the Medical Director of the GI Cancer Prevention Program Clinic at the Seattle Cancer Care Alliance, which specializes in the care of individuals who have cancer family syndromes.
He is an independent NIH funded PI with experience in the study of the molecular and cell biology of gastrointestinal cancer. He is the PI of an R01 funded study to assess the role of deregulated signaling pathways in the formation of colon cancer and is a recognized expert in the study of transforming growth factor ß (TGF-ß) signaling in colon cancer. He is also the PI of an Early Detection Research Network (NCI) Project to identify novel early detection markers for colon neoplasms as well as a project PI of a P01 (RecQ helicases and Colon Cancer) to identify predictive molecular markers for colorectal cancers. He has received numerous awards including the Damon Runyon-Lilly Clinical Investigator Award, Presidential Early Career Award for Scientists and Engineers, Burroughs Wellcome Clinical Scientist Award in Translational Research, and is a member of the American Society of Clinical Investigation.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video
William Grady gave a great lecture.
Since the audio to the first 2 slides didn’t record, we have retained the slides for the record but cut down their duration on screen. His audio now appears at 1’08.

A brief summery of the first 2 slides:

Colorectal cancer is one of the most common cancers that affects people around the world. In the United States, 155,000 people per year are diagnosed with colorectal cancer. Virtually all colon cancers develop from colon polyps, which are benign tumors called adenomas. These adenomas occur in 1/3 of people over the age of 40 and over time can become cancer. It takes roughly 10-15 years for an adenoma to become a cancer and only about 10{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of adenomas will become cancer. The long duration of the adenoma-carcinoma sequence has allowed a study of gene mutations that occurduring this process. Some mutations, such as APC (adenomatous polyposis coli gene) occur early in the process and are thought to initiate the formation of the adenomas, whereas others are found in more advanced adenomas or cancers and are thought to drive the progression of the adenomas to cancer.

Grady began by explaining that colorectal cancer takes many years – up to 2 decades to manifest from the initial event of a mutated cell in the colon epithelium to invasive cancer. He went on to describe how several different mutations are responsible for the development of cancer.

Date & Time: October 10th, 2011 12:00 p.m.

Title: The Role of Epigenetic Alterations in Colon Cancer

Abstract: Colorectal cancer arises as the consequence of the accumulation of genetic alterations (e.g. gene mutations, gene amplification, etc.) and epigenetic alterations (e.g. aberrant DNA methylation, chromatin modifications, etc.) that transform colonic epithelial cells into colon adenocarcinoma cells. The loss of genomic and epigenomic stability and resulting gene alterations appears to be a key molecular and pathogenic step that occurs early in the tumorigenesis process and permits the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes in a clone of cells to result in their ultimate transformation into cancer. It has also become clear that epigenetic alterations are common in many cancers and affect the formation and behavior of the tumors. With regards to DNA methylation, it is present normally throughout the majority of the genome and is maintained in relatively stable patterns that are established during development. In humans, approximately 70{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of CpG dinucleotides carry this epigenetic modification. However, there are regions that are enriched for CpG dinucleotides, called CpG islands, that are present in the 5’ region of approximately 50-60{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of genes and are normally maintained in an unmethylated state. In cancers, many of these CpG islands become aberrantly methylated, and this aberrant methylation can be accompanied by transcriptional repression. The significance of these epigenetic alterations in the pathogenesis of cancer has been a point of significant controversy. Nonetheless, there is sufficient data to demonstrate that the aberrant methylation of at least some of these genes, such as MLH1, can be pathogenetic in cancer. The aberrant methylation of MLH1 occurs in approximately 80{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of sporadic MSI colorectal cancers, and the restoration of MLH1 expression and function by demethylating the MLH1 promoter in MSI colorectal cancer cell lines, strongly supports the idea that such aberrant methylation is a cause rather than a consequence of colorectal carcinogenesis. Furthermore, the epigenetic inactivation of MLH1 appears to proceed the onset of mutations in genes with coding region microsatellite repeats, such as TGFBR2, suggesting epigenetic events can predispose tumor cells to mutations that drive the tumorigenesis process. Indeed, aberrantly methylated genes HLTF SLC5A8, MGMT, MINT1, and MINT31 can be found in aberrant crypt foci, demonstrating that aberrant promoter methylation occurs early in the adenoma sequence, although it does not confirm that the aberrant methylation is a primary rather than a secondary event in the tumorigenesis process. The aberrant methylation of genes affects genes that are commonly targets of mutational inactivation in colon cancers and contributes to the deregulation of signaling pathways that are known to be important in these tumors. Finally, a subset of colorectal cancers that hypermethylate genes belong to a distinct subclass of colorectal cancers, termed the CpG island methylator phenotype (CIMP) has been identified and appear to have a worse prognosis. These aberrantly methylated genes have been shown to be early detection markers and prognostic markers for a variety of cancers and some methylated genes are already being used in clinically available assays in the United States. The potential for methylated genes to be used as risk stratification markers, early detection markers, and predictive markers is high, and it is anticipated that they will move into common clinical use in the future. Finally, therapies directed at these genetic and epigenetic alterations are under active development and hold the promise to improve the treatment of colorectal cancer.

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
email hidden; JavaScript is required

Raoul Tibes – Target Identification in Cancer Using RNA interference – Accelerated Therapy Development in Leukemias

Wednesday, October 5th, 2011

Speaker: Raoul Tibes, MD, PhD. is a physician-scientist who sees and treats patients with hematological malignancies as well as heads laboratory research efforts in leukemia research. Further, he is actively conducting early phase (Phase 1/2) clinical trials with novel molecular therapies/agents.

Location: Biodesign Auditorium

Web Cast: Unavailable

Date & Time: November 17th, 2011 12:00 p.m.

Title: Target Identification in Cancer Using RNA interference –
Accelerated Therapy Development in Leukemias

Abstract: The challenge in drug development has been the implementation of novel active treatment regimens in cancer. Despite a deeper understanding of molecular oncogenesis many therapeutic strategies have failed in the clinic, raising the questions if currently developed drugs are not active enough against the targets or the “true” molecular targets – the synthetic lethal vulnerabilities in cancer genomes – have not been discovered yet.

Many therapeutic strategies were developed based on findings from structural molecular abnormalities such as mutations, amplifications or expression changes. However, functional information of interfering with the biological system (that is a cancer cell) and measuring the outcome after inhibiting individual genes is difficult to discern from these “static” research approaches. In order to obtain functional information of target gene interference that could be exploited for design of rational combinations in leukemias, our laboratory adopted small interfering RNA (siRNA) methodologies to suspension-leukemic cells in vitro. The challenge up to now has been the insufficient transfection of these leukemia cells for high-throughput siRNA (HT-siRNA). After successful establishment of a HT-siRNA platform for leukemia suspension cells, we performed the first cytotoxic drug-siRNA kinome sensitizer screen in leukemias. In siRNA kinome screens with the most commonly used leukemia drug Cytarabine, we identified a putative master sensitizer kinase in combination with Cytarabine. The target kinase and combination was validated in secondary siRNA screens and with a pharmacological inhibitor respectively. Based on these results a clinical trial has been proposed testing the identified rational combination.

A similar approach has been performed with 5-Azacytidine, a commonly used drug in myelodysplastic syndrome (MDS, often a pre-leukemia state). Of close to 900 genes individually silenced in combination with 5-Azacytidine, inhibition of only one genes potently sensitized to 5-Azacytidine. In validation experiments we confirmed the validity of this genes as a sensitizer to 5-Azacytidine by secondary siRNA screens. As well as showed strong sensitization of combining a novel small molecule inhibitor in clinical development targeting the identified gene, in combination with 5-Azacytidine, both in vitro and ex vivo. Clinical trials concepts have been developed for this novel combination as well.

Through the RNAi functional genomics approach we have identified new targetable concepts in myeloid cells alone or with commonly used leukemia drugs that yielded novel testable hypothesis to rapidly translate into clinical development and new treatment strategies in leukemias. These examples demonstrate the tremendous power and utility of functional genomics utilizing siRNA to identify, rational targets and combinations in cancer treatment.

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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Open Seminar – Luis Cisneros – Initiation of Micro-Metastases from Low-Fitness Cancer Cells: Rare, Explosive, and Deterministic

Thursday, September 22nd, 2011

Speaker: Luis Cisneros, PhD. works in the ASU Physics Department and the Beyond Center for Fundamental Questions in Science. He is interested in bio-fluid dynamics and collective phenomena of complex systems. He previously worked extensively in the collective behavior of suspensions of interacting motile bacteria, including experimental research, analysis and characterization of real data, development of models and test simulations. He is currently working on problems related to the migration and colonization processes of metastatic cancer cells, theoretical models of tumor proliferation and transition to malignancy, the Warburg effect and electrical properties of cancer cells.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: September 22nd, 2011 12:00 p.m.

Title: Initiation of Micro-Metastases from Low-Fitness Cancer Cells: Rare, Explosive, and Deterministic

Abstract:
The final stage of the metastatic cascade, colonization of secondary tissue sites, is very hard to address experimentally and is thus poorly understood. Given the long time-scale of most metastatic disease, it is commonly presumed that colonization arises from rare genetically pre-adapted founding cells. We construct a null model to estimate the relative probability of colonization from common non-pre-adapted cancer cells. We find that the dynamics of rare colonization events in this cell population is explosive and essentially deterministic, and thus indistinguishable from colonization dynamics from pre-adapted cells. And we find, in comparing relative likelihoods of pre-adapted and non-pre-adapted cells, that the latter can dominate if early metastatic tumors self-stabilize at a scale of 20-40 cells. We term this speculative tumor stage as a ‘proto-metastasis’, and comment on how these new insights may lead to new therapeutic interventions of metastatic disease. This is work in progress done in collaboration with Timothy Newman at The University of Dundee.

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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Open Seminar – David Fleischer, Mayo Clinic, Esophageal Cancer in Phoenix, Arizona and Feiching, China

Tuesday, August 23rd, 2011

Open Seminar – David Fleischer, Mayo Clinic, Comparing Esophageal Cancer in Phoenix, Arizona and Feiching, China
2011-08-25
12PM

Speaker: David Fleischer, Ph D. Gastroenterologist, Mayo Clinic.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: August 25th, 2011 12:00 p.m.

Title: Comparing Esophageal Cancer in Phoenix, Arizona and Feiching, China

Abstract:
There are approximately 16,000 cases of esophageal cancer each year in the United States and sadly, most patients die.. In contrast to the United States where adenocarcinoma is the primary histologic cause of cancer, worldwide, squamous cell carcinoma accounts for more than 80{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of cases.
With both types of histology, the prognosis and survival are linked closely to the stage at which the diagnosis is made. Therefore, for patients who present with symptoms of difficulty swallowing or weight loss, the cancer is usually advanced and the survival is less than 10{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb}. If it were possible to detect cancer in an earliest stage (for example stage I) or if a precursor lesion could be discovered, the survival would improve dramatically; if precursor lesions are discovered, survival can be more than 95{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb}.
There has been a great interest in the United States and other parts of the world for non-surgical endoscopic techniques such as endoscopic mucosal resection or ablation to manage and eliminate early esophageal cancers. Results from some of these studies will be discussed.
The collaborations between Mayo Clinic and Arizona State University provide an exciting opportunity for advances to diagnose, manage and ultimately prevent esophageal cancer.

Thank you and if you have questions please contact Pauline Davies! And don’t forget, coffee will be served!

Pauline Davies, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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Open Seminar – Robert H. Austin – Ten Crazy Ideas About Cancer

Monday, August 8th, 2011

Speaker: Robert Austin, Ph D. Professor of Physics and Director of the Princeton PS-OC.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: September 8th, 2011 12:00 p.m.

Title: Ten Crazy Ideas About Cancer

Abstract:
Although Paul Davies wanted me to talk about 10 Crazy Ideas for the Physics of Cancer, I have decided to pare the list down to 5. I am coming to the opinion that there are very deep concepts in biology which, while they may not be “new physics”, in a sense transcend what we usually view as things easily explained by the standard physics world-view. I also am forming the opinion that our failure to “cure” cancer, or even make substantial inroads into the mortality rate, indicates that there are things about biology and cancer that we as physicists miss using the standard physics world-view. I’ll try to give 5 examples of things physicists don’t get about biology, and cancer.

Thank you and if you have questions please contact Pauline Davies! And don’t forget, coffee will be served!

Pauline Davies, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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1:30PM – Open Seminar – Gaurav Sharma, Ph.D. ‘Therapeutic Targeting of Macrophages using Engineered Nanoparticles ‘

Thursday, February 17th, 2011

Gaurav Sharma

Speaker: Gaurav Sharma, Ph.D., Sanford Burnham Medical Research Institute, La Jolla, CA.

Location: John W. Schwada Building

Date & Time: Friday February 25th, 2011 1:30 p.m.

Web Cast: Unavailable

Summary:
Macrophages are versatile plastic cells that are key components of the body’s immune system. The interaction of engineered nanoparticles with macrophages is important because these cells clear nanoparticles from the circulation, and because they are potential therapeutic targets in inflammatory conditions, atherosclerosis and cancer. Therefore, an understanding of the features of engineered nanoparticles that influence their interaction with macrophages may allow optimization of their properties for enhanced drug delivery and imaging.
In the first part of this talk I will present results from a study where I showed that particle shape impacts phagocytosis by macrophages, and more importantly, that particle shape and size separately impact attachment and internalization. The study provides methodology for further exploring how particle shape can be controlled to achieve desired attachment and internalization. The results of the study also give mechanistic guidance on how particle shape can be manipulated to design drug carriers to evade macrophages, or alternatively to target macrophages.
In the second part, I will present results from a study where I investigated an alternate therapy for cancer by targeting and killing tumor associated macrophages (TAMs) that promotes tumor growth and metastasis. For this project, I designed nanoparticles that are loaded with an anti-macrophage drug and are actively targeted to TAMs in a mouse model of tumor and showed that these nanoparticles can selectively abrogate TAMs which leads to a suppression in tumor growth.

Thank you and if you have questions please contact Kaushal Rege, Assistant Professor of Chemical Engineering.
Email: email hidden; JavaScript is required Phone: 480-727-8616

Josh LaBaer – High Throughput Cell-Based Studies and Protein Microarrays for Biomarker and Target Discovery

Wednesday, February 16th, 2011

Josh Labaer

Speaker: Josh LaBaer,Ph D. Directory, Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video

Date & Time: Feb. 24th, 2011 12:00 p.m.

Title:High Throughput Cell-Based Studies and Protein Microarrays for Biomarker and Target Discovery
Summary:
One of the most compelling steps in the post-genomic era is learning the functional roles for all proteins. We have developed the FLEXGene Repository (for Full-Length Expression-ready), which comprises over 8000 full length clones for human genes, as well as complete genomes collections for several microorganisms enabling the high-throughput (HT) screening of protein function for the entire set (or any customized subset) of genes using any method of in vitro or in vivo expression.
The clones from the repository can be rapidly incorporated in HT biological experimentation. Using HT retroviral methods, proteins capable of inducing cancer-like behavior and conferring drug resistance can be tested. We derived a series of sub-cloned MCF7 cell lines that were either highly sensitive or naturally resistant to tamoxifen and studied the factors that lead to drug resistance. Gene expression studies revealed a signature of 67 genes that differentially respond to tamoxifen in sensitive vs. resistant subclones that also predicts disease-free survival in tamoxifen treated patients. High-throughput cell-based screens, in which >500 human kinases were independently ectopically expressed, identified 31 kinases that conferred drug resistance on sensitive cells. One of these, HSPB8, was also in the expression signature and, by itself, predicts poor clinical outcome in patients. Further studies revealed that HSPB8 protects MCF7 cells from tamoxifen and blocks autophagy. Moreover, silencing HSBP8 induces autophagy and causes cell death.

Click the slide above to view the presentation online

We developed a novel form of protein microarray, called nucleic acid programmable protein array (NAPPA). In lieu of producing and printing purified proteins, this method substitutes the printing of cDNAs encoding the proteins. Thus, the resulting array is a DNA array that can be converted into a protein array by adding cell free protein synthesis machinery. This obviates the need to purify proteins, produces human proteins in a mammalian milieu, and avoids concerns about protein stability on the array because the proteins are made just-in-time for assay. Moreover, the method displays a broad variety of proteins, insensitive to protein class or size with a high yield of protein per feature while maintaining a narrow range of protein yield from protein to protein.
NAPPA arrays can be used to study protein-protein interactions, protein-drug interactions, search for enzyme substrates, and as tools to search for disease biomarkers. In particular, recent experiments have focused on using these protein microarrays to search for autoantibody responses in cancer patients. Several bona fide autoantibody responses, such as responses to p53, have been detected, and a pilot study of responses to 7500 full length human proteins in 50 breast cancer patients and 50 controls has identified over 700 candidate proteins with more frequent responses in patients. These experiments show promise in finding antibody responses that appear in only cancer patients.

Thank you and if you have questions please contact Vanessa Baack! And don’t forget, coffee will be served!

Vanessa Baack, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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