bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A06: Exploring mechanisms of colorectal tumor radioresistance in organoids
Authors: Martin Maria Laura , Hua Guoqiang , Zeng Zhaoshi , Paty Philip B. 
Published: May 2016

Abstract
Colorectal cancer is the third most common cancer in men and the second in women worldwide. It is currently proposed that a population of tumor stem cells that are resistant to radiotherapy leads to tumor recurrence. Accumulating evidence indicates that a transformed lgr5+ [leucine-rich-repeat-containing G-protein-coupled receptor 5] cell at the base of the colonic crypt represents the cell of origin of colorectal cancer. However, mechanisms underlying colorectal cancer radioresistance are not completely understood. The purpose of this study is to elucidate mechanisms of resistance to radiation of normal and tumor stem cells. Using lgr5-lacZ transgenic mice we show that lgr5+ stem cells in the distal part of the large intestine are significantly more radiation resistant than their counterpart in the small intestine. In agreement with in vivo data, isolated colonic crypts are also significantly more resistant to radiation than small intestinal crypts in vitro. Additionally, using a mouse model of colitis-associated colon adenoma (azoxymethane - dextran sulfate sodium mouse model) we determined that crypt-like structures derived from mouse adenoma are even more radioresistant than normal colon. These results validate intestinal organoids as a model for in vivo radiation responsiveness. The next step is to elucidate mechanisms of radiation resistance of human colorectal stem cell organoids derived from normal tissues and tumors. The findings from this work will shed light on properties of lgr5+ tumor stem cells that may be relevant when devising strategies to reduce tumor burden.
Citation Format: Maria Laura Martin, Guoqiang Hua, Zhaoshi Zeng, Philip B. Paty. Exploring mechanisms of colorectal tumor radioresistance in organoids. [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 A06.
Abstract B18: Strand-specific in vivo screen of cancer-associated miRNAs unveils key drivers and oncogenic targets
Authors: Ge Yejing , Zhang Liang , Nikolova Maria , Reva Boris , Fuchs Elaine 
Published: May 2016

Abstract
MiRNAs are evolutionarily conserved small non-coding RNAs that orchestrate a wide spectrum of physiological and pathological processes in stem cells (SCs) and human cancers. Intimately wired into oncogenic and tumor suppressive networks, miRs are valuable as not only diagnostic biomarkers but also therapeutic targets. Squamous cell carcinomas (SCCs) are among the most life-threatening human cancers world-wide. Using skin as paradigm, we describe the first panoramic view of miRs during the development, homeostasis and malignant transformation of skin epithelium, whose SCs are the target of most common SCCs. Focusing on abundant and enriched miRs in SCC-SCs versus normal skin SCs, we devised lentiviral miR expression platform and conducted pooled in vivo functional screens for oncomiRs in mice. Deep sequencing of genomic DNA from basal progenitors of tumors or unaffected skin epithelium revealed preferential enrichment of 29/169 miRs within the tumors. We followed up with the top hits and showed candidate miRs are indeed aberrantly induced in both mouse and human SCCs. After functionally documenting their tumor-promoting roles in mouse SCCs in vivo and human xenografts, we applied CRISPR technology to ablate the miR loci in cells derived from these SCCs, and then used lentiviral delivery methods to carry out specific miR rescues of the tumorigenic phenotype. To look for candidate targets of newly identified oncomiRs, we analyzed TCGA database that are inversely correlated with our candidate miR as well as genes that are de-repressed upon miR deletion. We discovered potent tumor suppressors whose knockdown rescued the deficit in tumor formation from oncomiR-deficient cells and whose overexpression reversed miR-driven tumorigenesis. Furthermore, we demonstrated CRISPR-mediated deletion of the endogenous miRNA binding site renders the target cells no longer sensitive to miRNA regulation. Finally, we pinpointed the cellular mechanism of how miR-target regulates SCC progression. Empowered by mouse genetics and high throughput approaches, our study has unveiled a rich set of putative miRs that drive skin SCC malignancy, and discovered their oncogenic targets. These findings shed new light on increasingly important oncomiR loci and its action on a devastating cancer.
Citation Format: Yejing Ge, Liang Zhang, Maria Nikolova, Boris Reva, Elaine Fuchs. Strand-specific in vivo screen of cancer-associated miRNAs unveils key drivers and oncogenic targets. [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 B18.
Abstract B37: hnRNP K in acute promyelocytic leukemia cells NB4 and NB4-R2: Involvement in cell survival and differentiation
Authors: Padovani Karina Stringhetta , Annichini María Sol Brassesco , Rego Eduardo Magalhães , Curti Carlos , Greene Lewis Joel , Leopoldino Andréia Machado 
Published: May 2016

Abstract
hnRNP K has been reported to be overexpressed in myeloid leukemia and it is downregulated during all-trans retinoic acid (ATRA) induced differentiation of Acute Promyelocytic Leukemia (APL) cells. The aim of the present study was to establish role of hnRNP K in APL using responsive (NB4) and resistant (NB4-R2) cells to the all-trans retinoic acid treatment as well as the possible role of hnRNPK in ATRA-induced cellular differentiation. After demonstration, by Western blotting analysis, that hnRNP K is overexpressed (10 fold) in APL (NB4 and NB4-R2) cell lines compared to controls (bone marrow and polymorphonuclear cells), we knocked-down the protein by short hairpin RNA (shRNA) interference in these cell lines and assessed involvement of hnRNP K in ATRA-induced differentiation, by flow cytometry in cells incubated with Cd11bPE antibody, as well as the contribution of hnRNP K to proliferation, with growth curve, using Trypan Blue, and survival, by propidium iodide incorporation analysis in flow cytometer. The knockdown of hnRNP K in NB4 (72%) and NB4-R2 (60%) leads to loss of viability mainly in NB4-R2 (42,43% of viability) vs NB4 (75,33% of viability). The loss of viability was more accentuated after ATRA treatment, NB4-R2 (6,13% of viability) vs NB4 (70% of viability). hnRNP K knockdown increases APL cells differentiation and was more accentuated in association with ATRA treatment, NB4-R2 (+59,13%) vs NB4 ( +14,06%). Furthermore, knockdown of hnRNP K leads to decreased in proliferation in NB4 (-95,98%) and NB4-R2 (-97,5%). hnRNP K knockdown promotes decrease of Bcl-xl, PML-RARα, procaspase-3 and increases of SET protein levels in both cells, demonstrated by Western blotting. The extracellular signal-regulated kinase ERK is a positive hnRNP K regulator, so the treatment with the ERK inhibitor at 10 μM U0126 produces effects similar to hnRNP K knockdown on cell viability in NB4-R2 cells, and in levels of BCL-xl and SET proteins. We concluded that, hnRNP K knockdown decreases the cell proliferation and viability of NB4 and NB4-R2 cells and increases cell differentiation, via MEK-ERK-hnRNP K-SET signaling. hnRNP K represent a potential target in APL ATRA resistant cells.
Citation Format: Karina Stringhetta Padovani, María Sol Brassesco Annichini, Eduardo Magalhães Rego, Carlos Curti, Lewis Joel Greene, Andréia Machado Leopoldino. hnRNP K in acute promyelocytic leukemia cells NB4 and NB4-R2: Involvement in cell survival and differentiation. [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 B37.
Abstract IA23: Hippo/YAP signaling in stem cells and cancer
Authors: Camargo Fernando 
Published: May 2016

Abstract
The long-term goals of the Camargo laboratory are to provide basic insight into conserved mechanisms underlying size and growth control. We are particularly interested in the pathways that somatic stem and progenitors cells utilize to sense and respond to growth inputs in vivo. We utilize the mouse as a genetic model to study pathway function and to dissect the mechanisms by which growth control is coordinated. We also employ three-dimensional primary culture, biochemistry, and high-throughpout genetic interrogation in vitro to identify novel growth-control genes and to provide basic molecular mechanisms underlying our in vivo observations. Additionally, my lab is pursuing the development of novel technologies for lineage tracing of mammalian stem cells. We are particularly interested in studying the function of the Hippo/YAP signaling pathway and its effects on tissue size, homeostasis and cancer. We have demonstrated that Hippo signaling can be a very potent regulator of organ size in mice and have provided a conceptual link between organ size regulation and stem cell activity through Hippo signals. Studies exploring the molecular basis of YAP-driven phenotypes will be discussed.
Citation Format: Fernando Camargo. Hippo/YAP signaling in stem cells 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 IA23.
Abstract IA32: Identification and therapeutic targeting of poor prognosis subtypes in colorectal cancer
Authors: Batlle Eduard 
Published: May 2016

Abstract
About 40-50% of Colorectal Cancer (CRC) patients with locally advanced disease show resistance to therapy and develop recurrent cancer over the course of their treatment. Current CRC staging based on histopathology and imaging has a limited ability to predict prognosis. A major advance has been the elaboration of molecular classifications based on global gene expression profiles, which have defined CRC subtypes displaying resistance to therapy and poor prognosis. We have recently evaluated these molecular classification systems and discovered that their predictive power arises from genes expressed by stromal cells rather than by epithelial tumor cells. Our functional dissection of CRC progression shows that metastasis relies on a tumor cell non-autonomous program driven by TGF-beta in the microenvironment. Virtually all poor prognosis CRC subtypes upregulate this stromal gene program, which confers a survival advantage to metastatic stem cells during organ colonization. Here I will discuss our latest data about the dichotomy of TGF-beta signaling in epithelial versus stromal cells during CRC progression and the use of patient derived tumor organoids and mouse models to test the efficacy of anti-TGF-beta therapies for CRC treatment.
Citation Format: Eduard Batlle. Identification and therapeutic targeting of poor prognosis subtypes in colorectal 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 IA32.
Abstract PR04: Germline loss of PK-M2 promotes metabolic syndrome and hepatocellular carcinoma
Authors: Dayton Talya L. , Gocheva Vasilena , Miller Kathryn M. , Israelsen William J. , Clish Clary B. , Bhutkar Arjun , Davidson Shawn M. , Luengo Alba , Heiden Matthew G. Vander , Jacks Tyler E. 
Published: May 2016

Abstract
The pyruvate kinase gene, Pkm, encodes the PK-M1 and PK-M2 isoforms, which are the result of alternative splicing of mutually exclusive exons. While PK-M1 is considered the adult pyruvate kinase isoform, PK-M2 has been closely linked to embryogenesis, tissue regeneration, stem cells, and cancer. Nonetheless, expression of PK-M2 is widespread in wild-type embryonic and adult tissues. To interrogate the functional requirement for PK-M2, we generated and characterized germline PK-M2 null mice (Pkm2-/-). We found that Pkm2-/- mice are viable and express PK-M1 throughout embryogenesis and into adulthood. Strikingly, PK-M2 loss leads to spontaneous hepatocellular carcinoma (HCC) that is preceded by progressive metabolic disease characterized by insulin resistance, inflammation, and hepatic steatosis. Therefore, in contrast to its role in modulating metabolism to promote cancer in a cell-intrinsic manner, PK-M2 plays a role in maintaining systemic metabolism, thereby preventing metabolic syndrome and HCC. To further dissect the contrasting systemic and cell-intrinsic roles of PK-M2 in the context of cancer, we have combined autochthonous mouse models of cancer from our lab with both the germline null allele of Pkm2, Pkm2-/-, and the conditional allele of Pkm2, Pkm2fl/fl. This study will allow us to elucidate the distinct cell-intrinsic and cell-extrinsic roles of PK-M2 in both maintaining normal systemic metabolism and aberrant proliferation in the context of cancer.
This abstract is also presented as Poster B25.
Citation Format: Talya L. Dayton, Vasilena Gocheva, Kathryn M. Miller, William J. Israelsen, Clary B. Clish, Arjun Bhutkar, Shawn M. Davidson, Alba Luengo, Matthew G. Vander Heiden, Tyler E. Jacks. Germline loss of PK-M2 promotes metabolic syndrome and hepatocellular carcinoma. [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 PR04.
Abstract A08: The role of branched-chain amino acid metabolism in Myc-driven malignancies
Authors: Fernandez Mario R. , Damoulis Vanessa A. , Wang Wei , Radlwimmer Bernhard , Cleveland John L. 
Published: May 2016

Abstract
Cancer cells have high metabolic demands. Myc oncoproteins function as transcription factors and are overexpressed in a number of human malignancies. Myc induces the transcription of a number of genes involved in glycolysis and glutaminolysis, including those encoding transporters of glucose, glutamine, lactate and branched-chain amino acids (BCAA: valine, leucine and isoleucine, via LAT1/SLC7A5). Tumors driven by Myc are dependent on and utilize L-glutamine to feed carbon intermediates into the Krebs Cycle. We reasoned that Myc would also control the catabolism of BCAA, which also provides key metabolic intermediates, specifically acetoacetate, acetyl-CoA, proprionyl-CoA, NADH and FADH2. Consistent with this notion, expression analysis of premalignant and neoplastic B cells of Eμ-Myc transgenic mice, a validated model of human B cell lymphomas with Myc involvement, showed elevated mRNA and protein levels of BCAT1, which is a bona fide Myc transcription target and the first enzyme in BCAA catabolism. Further, elevated levels of several other enzymes involved in BCAA catabolism manifest in Eμ-Myc B cells. To assess the role of BCAT1 in tumor cell growth and survival, human B cell lymphoma and ovarian tumor cell lines that express high levels of BCAT1 were engineered to inducibly express shRNA that selectively silences BCAT1 expression. Notably, BCAT1 knockdown impaired tumor cell growth and survival, and long-term clonogenic growth. Moreover, treatment of Eμ-Myc B cells and BCAT1 overexpressing human tumor lines with a known BCAT1 inhibitor, Gabapentin, compromises growth and survival. Finally, the roles of BCAT1 in tumor maintenance in vivo will be presented. These findings lay the foundation for targeting BCAA catabolism in human tumors and tumor subtypes having MYC/MYCN involvement.
Citation Format: Mario R. Fernandez, Vanessa A. Damoulis, Wei Wang, Bernhard Radlwimmer, John L. Cleveland. The role of branched-chain amino acid metabolism in Myc-driven malignancies. [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 A08.
Abstract A39: Identification and biostatistical analysis of conserved metabolic profiles in breast tumors from transgenic mouse models
Authors: Dai Chen , Littlepage Laurie , Li Jun 
Published: May 2016

Abstract
Novel breast biomarkers with prognostic and therapeutic value include metabolites that are differentially expressed in breast tumors. The goal of this study is to identify global metabolic profiles of breast tumors derived from multiple established transgenic mouse models to gain insight into breast cancers of differing origin. We compared breast tumor samples to normal tissue and between cancer models from transgenic mouse breast cancer models overexpressing the following oncogenes: PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg transgenic mice. Our breast tissue samples were analyzed on GC-MS and LC-MS/MS platforms, and analysis included 374 biochemical compounds of known identity.
Comparison of global metabolic profiles between the different mouse breast cancer and normal tissue revealed many metabolic differences between genetic models. The vast majority of metabolomic profiles demonstrated differential levels of biochemicals between normal and tumor tissues consistent with changes in metabolism that support rapid growth. Breast tumors had increased glucose metabolism, amino acid metabolism, catabolism, and levels of the TCA cycle intermediates, consistent with increased energy production and anaplerotic contributions from amino acid catabolism. We also saw increased phospholipid metabolism, cholesterol uptake, and nucleotide metabolites.
Combined with published gene expression data for these mouse models, we were able to conduct biostatistical analysis to search for correlation between gene expression and metabolite levels. We identified novel key metabolites and genes that correlate with the most other metabolites/genes; the list of these “hub” metabolites/genes could prove to be novel sites of regulation for breast cancer progression.
We identified novel metabolic profiles of breast cancer that will be foundational in identifying metabolites with clinical prognostic value. Currently we are using both 3D culture and preclinical animal models to examine the role of the differentially expressed metabolites in breast cancer progression and treatment.
Citation Format: Chen Dai, Laurie Littlepage, Jun Li. Identification and biostatistical analysis of conserved metabolic profiles in breast tumors from transgenic mouse models. [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 A39.
Abstract A42: Exploring differential metabolic plasticity for treatment of cancer
Authors: Rodriguez-Colman Maria J. , Meerlo Maaike , Verhoeven-Duif Nanda , Burgering Boudewijn 
Published: May 2016

Abstract
The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis even in the presence of sufficient oxygen concentration to perform OXPHOS in mitochondria. In the last years the understanding of cancer metabolism has increased, revealing its high complexity. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as deregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore recently, there is a renewed interest in targeting metabolism as a resource for cancer treatment options. However, cancer heterogeneity and the variable mutational spectrum of cancer will likely hamper targeting metabolism in a manner similar to targeting deregulated signal transduction. Our work aims to analyze and correlate common cancer mutations with metabolic changes and thereby to rationalize metabolic personalized cancer treatment. For this purpose we combine metabolic measurements from genetically defined colon organoids (tumor progression organoid model and organoids derived from various genetically modified mice) and patient derived colon tumor organoids (biobank) from which the genome has been fully sequenced. Metabolism is profiled by various methods including Seahorse technology for the determination of bioenergetics, and untargeted metabolomics. This enables us to profile these organoids based on their metabolic program and to use this information for specific cancer treatment.
Citation Format: Maria J. Rodriguez-Colman, Maaike Meerlo, Nanda Verhoeven-Duif, Boudewijn Burgering. Exploring differential metabolic plasticity for treatment of 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 A42.
Abstract A62: Chemoresistance through the intratumoral metabolism of dichloroacetate
Authors: Jahn Stephan C. , Solaymen Mohamed H. , Lorenzo Ryan J. , Langaee Taimour , Stacpoole Peter W. , James Margaret O. 
Published: May 2016

Abstract
Dichloroacetate (DCA), a small molecule commonly used to treat metabolic disorders, is under investigation as an anti-cancer therapy due to its ability to reverse the Warburg effect and induce apoptosis. While DCA's mechanism of action is well-studied, other factors that influence its success as a cancer treatment have not been thoroughly studied. Here we present data showing that expression of glutathione transferase zeta 1 (GSTZ1), the enzyme responsible for the metabolism of DCA, is often misregulated in cancer, resulting in expression in tissues where there generally is none and a lack of expression in sites that have a high level of basal expression. Expression of GSTZ1 in a tumor would be expected to reduce intratumoral DCA concentrations. As we see a disconnect between GSTZ1 mRNA and protein expression in these tumors, control of expression is likely through miRNA. We also report that chloride concentrations, which strongly impact the stability of GSTZ1 in the presence of DCA, may be abnormal in tumors, further influencing DCA metabolism, concentration, and treatment success. Both two- and three-dimensional cell culture of cells expressing or not expressing GSTZ1 provide a proof of principle that GSTZ1 expression confers a level of resistance to DCA. These results have important clinical implications as GSTZ1 expression and chloride concentration could be used as markers to predict outcomes of DCA anticancer therapy.
Citation Format: Stephan C. Jahn, Mohamed H. Solaymen, Ryan J. Lorenzo, Taimour Langaee, Peter W. Stacpoole, Margaret O. James. Chemoresistance through the intratumoral metabolism of dichloroacetate. [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 A62.