bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA11: Functional and clinical relevance of intratumor heterogeneity in breast cancer
Authors: Polyak Kornelia 
Published: May 2016

Abstract
Intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. We have analyzed cellular genetic and phenotypic heterogeneity in breast tumors using immune-FISH and found that higher pre-treatment genetic diversity predicts therapy resistance and distant metastases are the most diverse. In HER2+ tumors we detected startling heterogeneity for HER2 copy number gain and PIK3CA mutation using STAR-FISH, a novel method we developed, and determined that changes in the topologic distribution of cellular heterogeneity for these genetic alterations during neoadjuvant chemotherapy predicts long-term clinical outcome.
We have also developed experimental models of subclonal heterogeneity and shown that polyclonal tumors grow faster and are more metastatic than monoclonal ones, a tumor-driver clone can be a minor subpopulation acting via non-cell-autonomous mechanisms, a dominant clone can outcompete the tumor-driver minor clone leading to tumor collapse, and that cancer therapies intensify clonal competition potentially leading to inadvertent acceleration of disease progression.
Our results emphasize the need to study tumors as a whole and to understand the properties of cancer cell populations that compose tumors and interactions among them to be able to predict tumor evolution during disease progression and cancer therapies.
Citation Format: Kornelia Polyak. Functional and clinical relevance of intratumor heterogeneity in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA11.
Abstract IA24: A stem cell program in early human metastatic breast cancer cells
Authors: Lawson Devon , Kessenbrock Kai , Werb Zena 
Published: May 2016

Abstract
Metastasis is the process that leads to the poor prognosis in breast cancer. Understanding the processes involved in the initiation and progression of metastasis is critical for developing new preventative and therapeutic strategies. One hypothesis states that metastases arise from rare tumor cells that resemble stem cells in their ability to initiate and propagate tumors. In this study we used single-cell analysis to demonstrate that the initial disseminating metastatic cells resemble stem cells in their gene expression. We exploited patient-derived xenograft (PDX) models of human breast cancer to analyze metastatic cells in peripheral tissues. We developed a highly sensitive FACS-based assay to isolate and enumerate these metastatic cells. The primary tumor cells were heterogeneous and expressed high levels of luminal differentiation genes The metastatic cells from tissues with a low metastatic burden showed increased expression of stem cell, EMT, pro-survival, and dormancy-associated genes and differential expression of genes depending on the peripheral tissue. In contrast, in macrometastases, the cells were similar to primary tumor cells. The stem cell-like metastatic cells from low-burden tissues had significant tumor-initiating capacity upon transplantation, and differentiated to produce cancer cells with luminal gene expression. As the metastases progressed to a high metastatic burden the tumor cells showed increased expression of cMYC and proliferation-related genes. Our studies suggest that metastases are initiated by cells with stem cell character that upon proliferation and differentiation produce advanced metastatic disease and a poor outcome.
References:
Cheung, K.J., E. Gabrielson, Z. Werb & A. J. Ewald (2013). Collective invasion in breast cancer requires a conserved basal epithelial program. Cell. 155: 1639-1651.
Plaks, V., N. Kong & Z. Werb (2015). The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16: 225-238.
Lawson, D. A., N. Bhakta, K. Kessenbrock, K. Prummel, Y. Yu, K. Takai, A. Zhou, H. Eyob, S. Balakrishnan, C.-Y. Wang, P. Yaswen, A. Goga & Z. Werb (2015). Single-cell analysis reveals a stem cell program in early human metastatic breast cancer cells. Nature. In press.
Citation Format: Devon Lawson, Kai Kessenbrock, Zena Werb. A stem cell program in early human metastatic breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA24.
Abstract A30: AKT activation as a mechanism of escape from TGFβ-mediated lethal EMT
Authors: Huang Yun-Han , David Charles , Massague Joan 
Published: May 2016

Abstract
Frequent inactivation of transforming growth factor β (TGFβ) pathway core components in pancreatic ductal adenocarcinoma (PDA), especially the transcription factor SMAD4, suggests that TGFβ signaling is tumor suppressive in the pancreas. Yet, 50% of PDA retains an intact core TGFβ pathway, suggesting that there are mechanisms by which these tumors escape TGFβ-mediated tumor suppression. In unpublished work, we have delineated a mechanism for TGFβ-mediated tumor suppression via a lethal epithelial-mesenchymal transition (EMT). Based on clinical and in vitro evidence that AKT activation may suppress the lethal EMT response to TGFβ, we are investigating the role of AKT signaling in directly interfering with TGFβ-mediated tumor suppression. We have taken two major approaches: (1) to test the concept that AKT inhibition may reactivate TGFβ-mediated tumor suppression, we are chemically inhibiting AKT in PDA mouse models competent and deficient in TGFβ signaling, and (2) to understand the mechanism of AKT-TGFβ crosstalk in PDA progression, we are performing RNAseq-based gene expression profiling of SMAD4-restored PDA cell lines. We have found that in vitro, AKT signaling determines whether TGFβ induces apoptosis in SMAD4-restored PDA cell lines, and by gene expression analysis, we have identified a group of genes that are differentially regulated by TGFβ in the presence and absence of AKT signaling. Furthermore, we have characterized FOXO immunohistochemical staining as a reliable marker for AKT inhibition status and developed an in vivo system in which we are testing whether AKT inhibition may be a means to reactivate TGFβ-mediated tumor suppression in PDA. Our studies indicate that AKT signaling may alter the outcome of TGFβ-mediated tumor suppression in the pancreas, and our ongoing work is aimed at dissecting the AKT-modulated transcriptional mechanisms that determine the outcome of TGFβ signaling and the consequences of this crosstalk in tumor progression.
Citation Format: Yun-Han Huang, Charles David, Joan Massague. AKT activation as a mechanism of escape from TGFβ-mediated lethal EMT. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A30.
Abstract A36: Notch signaling promotes tumor metastasis in the Pten null mouse model for prostate cancer
Authors: Kwon Oh-Joon , Zhang Li , Jianghua Wang , Creighton Chad , Ittmann Michael , Xin Li 
Published: May 2016

Abstract
The role of Notch signaling in prostate cancer remains inconclusive. We show that a higher Notch signature score is significantly correlated with higher disease grade, metastatic potential and higher probability of lethal outcome in two published human prostate cancer datasets. We employ genetic approaches to investigate the role of Notch signaling in initiation and progression of prostate cancer in a Pten null mouse model. Notch signaling is dispensable for disease initiation and progression in this model. Elevated Notch activity in the Pten null model promotes both epithelial proliferation and apoptosis, which collectively results in a reduction of primary tumor burdens. Despite reduced primary tumor burdens, Notch activation drives epithelial-mesenchymal-transition and promotes distal tumor metastases at full penetrance. Our study reveals distinct impacts of Notch signaling on cancer cell proliferation, survival and metastasis in the context of Pten loss, and highlights a multifaceted and pleiotropic role of Notch in regulating the different aspects of prostate cancer cell biology.
Citation Format: Oh-Joon Kwon, Li Zhang, Wang Jianghua, Chad Creighton, Michael Ittmann, Li Xin. Notch signaling promotes tumor metastasis in the Pten null mouse model for prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A36.
Abstract B06: Complex requirement of YAP and TAZ in gastrointestinal development and tumorigenesis
Authors: Cotton Jennifer L. , Li Qi , Ma Lifang , Ip Tony , Johnson Randy , Mao Junhao 
Published: May 2016

Abstract
YAP and TAZ are the major intracellular mediators of Hippo signaling in mammals; however, the precise function of YAP/TAZ in gastrointestinal development and tumorigenesis remains poorly understood. By specific removal of YAP/TAZ from the developing endoderm and gastrointestinal tract, we find that YAP/TAZ are dispensable for Wnt signal transduction and normal gastrointestinal epithelial differentiation, but act as the direct TCF4 targets and downstream effectors during epithelial transformation. Surprisingly, our loss- and gain-of-function genetic analyses identify an essential role for YAP/TAZ in the gastrointestinal mesenchyme as a molecular switch to coordinate growth and differentiation. We find that YAP/TAZ are required for the expansion of the primitive progenitor populations critical for mesenchymal growth. However, persistent YAP activation inhibits the induction of the smooth muscle lineage, and YAP/TAZ down-regulation during later development is essential for Hedgehog signaling-induced differentiation of smooth muscle cells. Taken together, our studies uncover a complex requirement of YAP/TAZ in the gastrointestinal tract and demonstrate the functional interplays among key signaling pathways during gastrointestinal development and tumorigenesis.
Citation Format: Jennifer L. Cotton, Qi Li, Lifang Ma, Tony Ip, Randy Johnson, Junhao Mao. Complex requirement of YAP and TAZ in gastrointestinal development and tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B06.
Abstract B08: Altering cellular differentiation and energy metabolism by the mTORC1 inhibitor NPRL2
Authors: Dutchak Paul A. , Terpack SandiJo , Tu Benjamin P. 
Published: May 2016

Abstract
Nitrogen permease regulator-like 2 (NPRL2) is a component of an evolutionarily conserved complex that inhibits mTORC1 (mechanistic Target Of Rapamycin Complex 1) in response to amino acid insufficiency. The NPRL2 complex functions as a GTPase activating protein against the RAG proteins, which are located on the lysosomal surface and stimulate mTORC1 activity when bound to GTP. Since the loss of NPRL2 expression is frequently associated with different types of cancers, including renal and lung, our aim is to investigate the biological function of NPRL2 in vivo and determine how this pathway can contribute to cancer growth. Previous data from our lab show that NPRL2 is required for mouse viability and that its absence significantly compromises fetal liver hematopoiesis in embryos with defective lysosomal processing of vitamin B12 and methionine/SAM homeostasis contributing to the phenotype. Here we show that loss of NPRL2 in muscle alters the differentiation of fiber-types, leading to increased size and number of glycolytic muscle fibers in the mice. Consistent with this phenotype, the NPRL2 muscle specific knockout mice show a sprinting phenotype and increased glucose utilization. These findings demonstrate that NPRL2 is able to regulate cellular differentiation patterns potentially by altering cellular methylation and represents a genetic link between amino acid metabolism and carbohydrate utilization, two hallmarks that are frequently altered in cancer.
Citation Format: Paul A. Dutchak, SandiJo Terpack, Benjamin P. Tu. Altering cellular differentiation and energy metabolism by the mTORC1 inhibitor NPRL2. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B08.
Abstract B13: ETC-159 is a novel PORCN inhibitor effective for treatment of Wnt-addicted genetically defined cancers
Authors: Madan Babita , Ke Zhiyuan , Harmston Nathan , Petretto Enrico , Hill Jeffrey , Keller Thomas H. , Lee May Ann , Matter Alex , Virshup David M. 
Published: May 2016

Abstract
Pathologic expression of Wnts is found in cancers, fibrosis and other diseases, hence there is considerable interest in blocking Wnt signaling to achieve therapeutic benefit. Post-translational palmitoleation of Wnts at a highly conserved serine residue is essential for their secretion and function. We have pursued a strategy to block all Wnt-dependent pathways concomitantly using a small molecule inhibitor of the enzyme PORCN that is required for Wnt O-palmitoleation. As Wnt pathway inhibitors advance to clinical trials, the paucity of well-defined biomarkers makes it challenging to monitor response to therapeutics.
We have developed a novel PORCN inhibitor ETC-159, which has remarkable efficacy in pre-clinical models of RNF43-mutant pancreatic and ovarian cancers and RSPO3-translocation bearing colorectal cancer patient derived xenografts. ETC-159 reverses Wnt dependent pathology by promoting cellular differentiation. Consistent with the role of Wnt/β-catenin signaling in regulation of diverse cellular functions, RNA sequencing of these ETC-159 sensitive, Wnt driven cancers has revealed significant remodeling of the transcriptome on treatment with ETC-159 with a decrease of cell cycle, stem cell, and proliferation genes and an increase in differentiation markers. Our studies show that coordinate regulation of NOTUM and AXIN2 gene expression may be a useful predictor of sensitivity to PORCN inhibitors. NOTUM is a secreted protein and its levels in serum correlate with tumor growth. Notum has potential to be a pharmacodynamic biomarker that will reflect a response to PORCN and other Wnt pathway inhibitors.
Citation Format: Babita Madan, Zhiyuan Ke, Nathan Harmston, Enrico Petretto, Jeffrey Hill, Thomas H. Keller, May Ann Lee, Alex Matter, David M. Virshup. ETC-159 is a novel PORCN inhibitor effective for treatment of Wnt-addicted genetically defined cancers. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B13.
Abstract IA01: Wnt signaling stem cell control and cancer
Authors: Nusse Roel 
Published: May 2016

Abstract
Our laboratory is interested in the growth, development and integrity of animal tissues, with a focus on stem cells. Wnt signaling is widely implicated in stem cell control, as a mechanism to regulate the number of stem cells in tissues, Using various cell labeling methods, we have described novel populations of stem cells in various tissues, including in the liver. In that tissue, we found that hepatocytes that reside in the pericentral domain of the liver demonstrate stem cell behavior. Although these cells are functional hepatocytes, they are diploid and thus differ from the mostly polyploid mature hepatocyte population. They are active in homeostatic cell replacement and therefore distinct from oval cells, which require injury for their induction. Adjacent central vein endothelial cells provide the essential source of Wnt signals for the hepatocyte stem cells and thereby constitute the liver stem cell niche. It is noteworthy that liver cancer is often characterized by loss of function mutations in negative components of the Wnt pathway, including Axin and APC. We suggest that pericentral hepatocyte stem cells, normally controlled by a paracrine Wnt signal, are precursors to liver cancer.
Citation Format: Roel Nusse. Wnt signaling stem cell control and cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA01.
Abstract IA07: The effect of cell of origin on GBM phenotype
Authors: Parada Luis F. 
Published: May 2016

Abstract
Current thinking about solid tumor biology is largely influenced by analysis of the large data sets afforded by modern genomic capabilities. In GBM, classification of tumors into four categories (proneural, neural, mesenchymal, and classic) relies on differential transcriptional profiles coupled with copy numbers, and mutational profiles. These approaches for example, imply EGFR receptor as a major driver of Classic sub-type whereas NF1 mutations are preferentially found in mesenchymal subtypes. Functional evidence that these molecular categories indeed reflect biologically different tumors remains to be proved. We have generated mouse models of GBM by driving loss of function of in the NF1, p53 and Pten tumor suppressors. We find that two phenotypically and biologically different GBMs emerge that reflect tumor initiation different adult CNS progenitor populations. Thus, in a mouse model, distinct progenitor cell populations dictate different tumors created by mutation in identical drivers.
Citation Format: Luis F. Parada. The effect of cell of origin on GBM phenotype. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA07.
Abstract A44: Expression of metabolic genes is associated with prognosis in breast cancer
Authors: Aiderus Abdul Aziz Bin , Black Michael A. , Dunbier Anita K. 
Published: May 2016

Abstract
Breast cancer is the most common malignancy and is the second leading cause of cancer-related death in American women. Approximately 75% of breast tumors express the oestrogen receptor, which can be targeted for with selective oestrogen receptor modulator such as tamoxifen, or by blocking oestrogen synthesis using aromatase inhibitors. However, approximately a quarter of patients treated for at least five years relapse with the disease within a decade. Many transcriptome studies have been conducted on breast tumor samples with clinical data to generate gene signatures predictive of treatment outcome. While several signatures have been reported, these features tend to be correlated with proliferation and give little information about the underlying tumor biology.
An emerging hallmark of cancer is the reprogramming of metabolic networks to meet the demand required for rapid growth of a tumor. Tumors are generally highly glycolytic to meet their energetic requirements, as well as to provide substrates for anabolic reactions necessary for cell growth. However, perturbations in other metabolic pathways that are essential for tumor development and growth remain poorly understood. In this study, we sought to identify and characterise molecular features associated with metabolism that are significantly correlated with breast cancer patient outcome. To achieve this, we performed Cox regression analysis on a training set of microarray gene expression data of 973 oestrogen-receptor positive breast tumors. To identify functional enrichment for the molecular features associated with disease-free survival, gene set enrichment analysis was performed. This analysis revealed a 19-gene signature involved in fatty acid metabolism that showed higher expression to be correlated with good prognosis in the training data (multivariate hazard ratio = 0.51, log-rank p = 2.23e-10). The prognostic performance of this signature was validated on an independent dataset (n=654, multivariate hazard ratio = 0.66, log-rank p = 6.51e-5). Using the online KMplotter software, the fatty acid metabolism signature was found to also be prognostic in both lung cancer (n=1926, univariate hazard ratio = 0.58, log-rank p = 1.1e-16) and gastric cancer (n=593, univariate hazard ratio = 0.73, log-rank p = 0.0012).
Based on our bioinformatic findings, we hypothesise that tumors with lowered fatty acid metabolism are more likely to exhibit invasive properties. Current work is focused on understanding how modulating fatty acid metabolism affects tumor biology, and may present a therapeutically tractable process that can be targeted with existing drugs.
Citation Format: Abdul Aziz Bin Aiderus, Michael A. Black, Anita K. Dunbier. Expression of metabolic genes is associated with prognosis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A44.
Abstract A54: Changes in fatty acid profile indicate a chemo-preventive response to navy bean extract in an inflammation-associated colorectal cancer mouse model
Authors: Perera Thushanthi H. , Young Matthew R. , Saud Shakir M. , Dextras Christopher R. , Jones-Hall Yava L. , Karoly Edward D. , Sampey Brante P. , Kim Young S. , Colburn Nancy H. , Bobe Gerd 
Published: May 2016

Abstract
Introduction: Consumption of dry beans and their fractions decrease colorectal neoplasia; however, the underlying molecular mechanisms are unclear. Aim of the study was to identify response indicators of dietary attenuation of colorectal tumorigenesis using metabolic profiling.
Methods: The study had a 2 x 2 factorial design. After being either induced or not with azoxymethane/dextran sodium sulfate (AOM/DSS), male FVB/N mice were fed an AIN93G diet containing either 0 (Control) or 10% navy bean ethanol extract (BE) for 6 weeks. Colon tissue was collected and analyzed for colitis, aberrant cell proliferation, and tumor, whereas serum, feed, and fecal samples were analyzed for metabolite levels.
Results: Dietary BE attenuated AOM/DSS-induced chronic colitis, aberrant epithelial cell proliferation, fecal blood (heme), and tumorigenesis (-40%; P=0.02) in the colon. Similar changes were observed for fecal medium-chain fatty acids (hexanoate, octonoate) and plant phenolics (vanillate) and serum markers of fatty acid oxidation (carnitine, hexanoylcarnitine), and the pentose phosphate pathway (sedophetulose-7-phosphate). Moreover, dietary BE increased fecal markers of apoptosis (ribose, uracil, pseudouridine, xanthine, hypoxanthine) and attenuated the AOM/DSS-induced decrease in serum glycerophosphocholine.
Conclusions: Dietary BE may inhibit survival and proliferation of premalignant colorectal epithelial cells by promoting fatty acid oxidation and resolving inflammation.
Citation Format: Thushanthi H. Perera, Matthew R, Young, Shakir M. Saud, Christopher R. Dextras, Yava L. Jones-Hall, Edward D. Karoly, Brante P. Sampey, Young S. Kim, Nancy H. Colburn, Gerd Bobe. Changes in fatty acid profile indicate a chemo-preventive response to navy bean extract in an inflammation-associated colorectal cancer mouse model. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A54.