bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY21-03: Skin stem cells in morphogenesis and cancer.
Authors: Fuchs Elaine , Beronja Slobodan , Schober Markus 
Published: August 2014

Abstract
Stem cells have the ability to self-renew long term and differentiate into one or more tissues. Typically, stem cells are used sparingly to replenish cells during normal homeostasis. This is particularly true of adult tissues that undergo relatively infrequent or periodic turnover. However, even stem cells that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How stem cells balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. Moreover, increasing evidence suggests that the regulatory circuitry governing this balancing act is at the root of some types of tumors both in mice and in humans.
We've been using skin as a paradigm to understand how stem cells function in normal tissue generation and how this process goes awry in cancer. We've elucidated many of the pathways involved in how extrinsic signaling mobilizes stem cells to make tissue. In so doing, we have revealed mechanisms which are also deregulated in a variety of different human cancers. This has led us to the realm of identifying cancer stem cells (tumor-initiating cells) of squamous cell carcinomas of the skin. The second most abundant form of cancer world-wide, skin squamous cell carcinomas also establish a paradigm for many life-threatening cancers of lung, esophagus, breast, cervix, prostate, throat and oral tissues. We've demonstrated that when purified and transplanted serially into the skins of host recipients, a single cancer stem cell from a skin squamous cell carcinoma can generate a new squamous cell carcinoma that is similar in properties to the parent tumor. We've also discovered that cancer stem cell numbers and aggressiveness are predicated on the tumor microenvironment and on the ability of cancer stem cells to respond to it. The striking differences between the microenvironments of cancer stem cells and their normal counterparts seems likely to contribute to why their expression profiles are also markedly distinct.
These findings underscore the importance of dissecting the molecular mechanisms of tumor progression and growth in vivo. To this end, we've developed a non-invasive method to knockdown genes rapidly, efficiently and selectively in the skin epithelium. We've exploited this technology to carry out a whole genome-wide screen in mice for genes that are selectively involved in regulating oncogenic growth in the skin. Our findings have major implications for our understanding of tumor progression and cancer.
[This work was supported by the HHMI and a grant from the National Institutes of Health]
Citation Format: Elaine Fuchs, Slobodan Beronja, Markus Schober. Skin stem cells in morphogenesis and cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY21-03. doi:10.1158/1538-7445.AM2013-SY21-03
Abstract SY21-04: Wnt signaling, stem cells, and cancer.
Authors: Nusse Roel 
Published: August 2014

Abstract
We are interested in the regulation of growth, development and integrity of animal tissues. We study multiple different organs, trying to identify common principles, and extend these investigations to cancer and injury repair. In most organs, different cell types are generated by stem cells; cells that also make copies of themselves and thereby maintain the tissue. A right balance between the number of stem and differentiated cells is essential for the proper function of the organs. Locally acting signals are important to maintain this balance in a spatially organized manner and these signals are key to understanding the regulation of growth. A common theme linking the work together is the Wnt family of signals. Work from many laboratories has shown that Wnt proteins are essential for the control over stem cells. How this is achieved is far from clear and is the subject of studies in the lab, both in vivo and in cell culture. In vivo, a particular question we address is how physiological changes, such as those occurring during hormonal stimuli, injury or programmed tissue degeneration have an impact on the self-renewal signals and on stem cell biology.
Current research includes: 1) Identifying and tracing Wnt-responsive stem cells in tissues; 2) mapping cis-acting transcriptional control elements (enhancers) that control Wnt gene expression in normal and injured tissues; 3) the use of active Wnt proteins to maintain stem cells (including embryonic stem cells) in cell culture; 4) presenting Wnt protein in a vectorial manner to stem cells to direct asymmetric cell division.
Citation Format: Roel Nusse. Wnt signaling, stem cells, and cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY21-04. doi:10.1158/1538-7445.AM2013-SY21-04
Abstract SY27-04: Engineering improved cancer vaccines.
Authors: Dranoff Glenn 
Published: August 2014

Abstract
Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits. We demonstrated that vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplishes clinically significant tumor destruction with minimal toxicity in a majority of stage IV metastatic melanoma and some advanced ovarian carcinoma patients. The extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs, suggesting that further Treg inhibition might increase the frequency of clinical responses. Through an analysis of cytokine deficient mice, we delineated a critical role for GM-CSF in Treg homeostasis. GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity. The pharmacologic inhibition of MFG-E8 function through genetic or engineering-based approaches blocks Treg induction, which intensifies vaccine-induced responses, leading to the regression of established tumors in mice. The clinical translation of these therapeutic strategies to Phase I testing in humans is underway.
The detailed analysis of patients achieving sustained clinical benefits from irradiated, autologous GM-CSF secreting tumor cell vaccines and CTLA-4 antibody blockade also affords a rich opportunity to identify antigens associated with immune-mediated tumor destruction and to delineate mechanisms of therapeutic immunity. We elucidated several of the molecular pathways that underlie these anti-tumor effects, including the NKG2D system and multiple secreted/or cell surface proteins that contribute to tumor promoting inflammation. The therapy-induced antibodies manifest functional activity in vitro, antagonizing tumor cell survival, invasive potential, and angiogenesis. These findings support a key role for humoral immunity in tumor destruction, and highlight interest in more detailed characterization of the anti-tumor B cell repertoire in vaccinated patients.
Citation Format: Glenn Dranoff. Engineering improved cancer vaccines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY27-04. doi:10.1158/1538-7445.AM2013-SY27-04
Abstract SY29-03: Following single mRNAs from birth to death in living cells and tissues.
Authors: Singer Robert 
Published: August 2014

Abstract
Imaging has been an essential tool to analyze the dynamic properties of RNA. New technologies in optical microscopy and tagging methods have allowed us to detect and track individual mRNA molecules in single living cells, yielding insights that could not have been obtained through any ensemble measurement: for instance in measuring the time for transcription elongation or nuclear pore transport. We have been dedicated to developing and implementing these technologies to further the understanding of dynamics of mRNA regulation in cells. We have utilized various microscopic approaches to analyze the components of real-time transcription of endogenous genes in living tissues of a transgenic mouse where the mRNAs are labeled by a fluorescent RNA binding protein. These approaches employ a plethora of imaging techniques, ranging from confocal and multiphoton microscopy, long-term cell imaging, high-speed real-time widefield microscopy, single molecule tracking, super-registration microscopy and fluorescence fluctuation analysis. The kinetics of the key elements of RNA metabolism: initiation, elongation, termination, as well as nuclear pore export, cytoplasmic trafficking, localization, translation and decay are now tractable at the single molecule level in vivo. By using mathematical modeling to extract the quantitative parameters of these kinetics, we can describe these processes precisely in living cells, leading to an understanding of the regulatory events governing gene expression-fundamental to the mechanism of disease.
Supported by NIH GMS Grants to RH Singer.
Citation Format: Robert Singer. Following single mRNAs from birth to death in living cells and tissues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY29-03. doi:10.1158/1538-7445.AM2013-SY29-03
Abstract SY33-02: Understanding the dynamics of cancer: From developmental pathways to in vivo imaging.
Authors: Reya Tannishtha 
Published: August 2014

Abstract
Our research focuses on the signals that control hematopoietic stem cell self-renewal and differentiation, how these signals are utilized during regeneration and how their dysregulation may lead to cancer. Using a multitude of genetic models, we have shown that classic developmental signaling pathways such as Wnt, Hedgehog and Notch play key roles in stem cell growth and regeneration and are dysregulated during leukemia development. In addition, we have used real-time imaging strategies to show that hematopoietic stem cells have the capacity to undergo both symmetric and asymmetric division, and that shifts in the balance between these modes of division are controlled by the microenvironment and subverted by oncogenes. Importantly, we have shown that regulators of this process, including the cell fate determinant Musashi, can promote aggressive cancers and could serve as critical targets for diagnostics and therapy. Most recently, we have developed a high resolution in vivo imaging system that has allowed us to begin to map the behavior and interactions of hematopoietic stem cells with the microenvironment within living animals, and to define how these change during regeneration and cancer formation.
Citation Format: Tannishtha Reya. Understanding the dynamics of cancer: From developmental pathways to in vivo imaging. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY33-02. doi:10.1158/1538-7445.AM2013-SY33-02
Abstract SY36-01: Exploiting intra-tumor heterogeneity through agent-based models of tumor growth to infer properties of human malignancies.
Authors: Sottoriva Andrea , Ma Zhicheng , Kang Haeyoun , Curtis Christina 
Published: August 2014

Abstract
In recent years, intra-tumor heterogeneity (ITH) has emerged as a fundamental property of many solid tumors. This feature is the product of cancer evolution and may be implicated in malignant progression and clinical outcome. ITH not only reflects the sequence of malignant events that have occurred in the neoplasm, but it also embeds a signature of the past proliferative history of tumor cells. This signature can be exploited to infer tumor dynamics and to measure properties of the cellular organization that render each cancer distinct. In particular, by integrating multiple types of genomic data derived from different regions of an individual tumor, with a 3-dimensional agent-based model of tumor growth, we can infer clinically relevant cancer parameters directly in human samples. This approach is highly flexible, enabling several malignant processes to be considered, and provides a natural framework with which to interpret the apparent complexity of cancer genomic data, with implications for understanding mechanisms of tumor progression. We demonstrate the utility of this approach on a cohort of breast and colorectal cancers.
Citation Format: Andrea Sottoriva, Zhicheng Ma, Haeyoun Kang, Christina Curtis. Exploiting intra-tumor heterogeneity through agent-based models of tumor growth to infer properties of human malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY36-01. doi:10.1158/1538-7445.AM2013-SY36-01
Abstract A06: A novel cell line model of the alternative lengthening of telomeres (ALT) telomere maintenance mechanism
Authors: Heaphy Christopher M. , Haffner Michael C. , Meeker Alan K. 
Published: August 2014

Abstract
Unlimited replicative capacity is a key hallmark of cancer that requires the abrogation of telomere attrition due to the end-replication problem. The vast majority of tumors maintain telomere lengths by expressing the enzyme telomerase; however, a subset utilizes a cancer-specific, telomerase-independent telomere maintenance mechanism, termed Alternative Lengthening of Telomeres (ALT). We recently uncovered a strong correlation between ALT and recurrent cancer-associated somatic inactivating mutations in the ATRX and DAXX genes. The ATRX and DAXX proteins form a chromatin remodeling complex with histone chaperone activity, targeting incorporation of the histone variant H3.3 to G-rich repetitive regions of the genome, including the telomeres, which are known to normally be maintained in a repressed heterochromatic state. Here, we have developed an isogenic cell line pair derived from first generation telomerase knock-out (KO) mouse embryonic fibroblasts. Compared to early-passage telomerase KO cells and late passage WT control cells, late-passage telomerase KO cells spontaneously developed the ALT phenotype. These ALT(+) cells display increased DNA damage, as observed by dramatically increased accumulation of γH2AX foci. We plan to use this unique cell line to identify drugs exhibiting selective toxicity for ALT(+) cells. Preliminary results indicate that ALT(+) late-passage telomerase KO cells exhibit an increased sensitivity to the DNA-PK inhibitor NU7441 compared to the isogenic early-passage ALT(-) telomerase KO cells. The identification of bona fide ALT-specific drugs will pave the way for the development of new targeted treatments for the significant number of cancers that harbor this unique molecular phenotype.
Citation Format: Christopher M. Heaphy, Michael C. Haffner, Alan K. Meeker. A novel cell line model of the alternative lengthening of telomeres (ALT) telomere maintenance mechanism. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A06.
Abstract A07: Characterizing the specific oncogenic and tumor suppressor roles of H3K27me3 epigenetic modulators in T cell leukemia
Authors: Ntziachristos Panagiotis , Tsirigos Aris , Trimarchi Thomas , Loizou Evangelia , Luyao Xu , Vlierberghe Pieter Van , King Bryan , Welstead Grant , Mullighan Charles , Jaenisch Rudolf , Ferrando Adolfo , Aifantis Iannis 
Published: August 2014

Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In a recently published work, we identified and characterized a tumor suppressor role for the Polycomb Repressive Complex 2 (PRC2), that was underlined through the identification of loss-of-function mutations and deletions of members of the PRC2 complex in 25% of the patients with T cell leukemia. Further inhibition of PRC2 action in T cell leukemia comes through competition with master oncogenes, such as Notch1, for chromatin binding. Extending our work on the H3K27me3 mark, we now show that the activity of the corresponding H3K27me3 demethylases is also very important for the initiation, progression and maintenance of the disease. More specifically, transcriptional data analysis and exome sequencing of primary T-ALL samples demonstrates a significant correlation between levels and mutational status of these demethylases and major oncogenic pathways in leukemia. Functionally, genomic ablation of these epigenetic modulators as well as targeting with a specific-recently produced and characterized-inhibitor-GSKJ4, leads to apoptosis and cell cycle arrest of T-ALL lines in vitro and in vivo, accompanied by major epigenetic and transcriptional changes at specific anti-apoptotic, oncogenic and metabolic genes. Furthermore, genetic ablation of these epigenetic modulators leads to slower initiation of the disease in a classic mouse model of leukemia with highly improved survival rates. In light of recent developments of novel epigenetic inhibitors against these molecules, these findings pave the way to specific pharmacological targeting of T cell leukemia.
Citation Format: Panagiotis Ntziachristos, Aris Tsirigos, Thomas Trimarchi, Evangelia Loizou, Xu Luyao, Pieter Van Vlierberghe, Bryan King, Grant Welstead, Charles Mullighan, Rudolf Jaenisch, Adolfo Ferrando, Iannis Aifantis. Characterizing the specific oncogenic and tumor suppressor roles of H3K27me3 epigenetic modulators in T cell leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A07.
Abstract A17: Glycosaminoglycans regulates histone acetylation status in multiple myeloma
Authors: Purushothaman Anurag , Sanderson Ralph D. 
Published: August 2014

Abstract
Histone acetylation modulates gene expression, cellular differentiation, and cell survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells and therefore HADC inhibitors are being actively studied as novel therapies in multiple myeloma. However, the mechanisms that regulate the acetylation levels of histones in myeloma remain unclear. We recently discovered that glycosaminoglycan (GAGs) chains of myeloma cells play an important role in regulating histone acetylation status. GAGs, such as chondroitin sulfate and heparan sulfate, which are expressed in the form serglycin and syndecan-1 proteoglycans, respectively, are highly expressed by myeloma cells and are present in the nucleus of these cells. Because exogenous GAGs are shown to both inhibit HAT activity and bind to the acetylation sites of histones, we hypothesized that reduction in GAGs would increase HAT activity and histone acetylation. We found that removal of GAGs from the nucleus of myeloma cells either by treatment with GAG degrading bacterial enzymes or by expressing the heparan sulfate degrading enzyme heparanase, significantly increased HAT activity and histone acetylation in myeloma cells. Further, the levels of acetylated histones are highly upregulated in tumors formed from cells expressing high levels of heparanase or cells that are silenced for syndecan-1 expression. BIACore assay showed that both chondroitin and heparan sulfates strongly bind to HAT enzyme p300. By dot blot assay we also demonstrate that both syndecan-1 and serglycin bind strongly to histones. Previous studies have shown that the negatively charged GAGs can bind to positively charged lysine residues (acetylation sites) on histone proteins. Overall our findings clearly demonstrate that GAGs decreases histone acetylation by both inhibiting HAT activity and by binding to acetylation sites of histones. This represents a novel mechanism for histone hypoacetylation, which is traditionally considered due to HDAC activity.
Citation Format: Anurag Purushothaman, Ralph D. Sanderson. Glycosaminoglycans regulates histone acetylation status in multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A17.
Abstract A19: The histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and proliferation
Authors: Malatesta Martina , Steinhauer Cornelia , Squatrito Massimo , Helin Kristian 
Published: August 2014

Abstract
The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of an aberrant Hh-Gli signaling has thus emerged as an attractive target for anticancer therapy, however the mechanisms that mediate Hh-Gli signaling in vertebrates remain still poorly understood. Here, we show that the histone acetyltransferase (HAT) PCAF/KAT2B is an important regulator of the Hh pathway. Specifically, we demonstrate that PCAF depletion leads to an impairment of Hh activity and reduced expression of Hh target genes. Consequently, downregulation of PCAF in medulloblastoma and glioblastoma cell lines leads to decreased cell proliferation and increased apoptosis. Furthermore, we show that PCAF interacts with GLI1, the downstream effector in the Hh-Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Our study identifies the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, and we propose PCAF as a potential interesting novel therapeutic target for the treatment of patients with medulloblastoma and glioblastoma.
Citation Format: Martina Malatesta, Cornelia Steinhauer, Massimo Squatrito, Kristian Helin. The histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and proliferation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A19.