bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-126: ARID1B is a specific vulnerability in ARID1A-mutant cancers
Authors: Helming Katherine , Wang Xiaofeng , Wilson Boris , Vazquez Francisca , Haswell Jeffrey , Manchester Haley , Kim Youngha , Kryukov Gregory V. , Ghandi Mahmoud , Aguirre Andrew J. , Jagani Zainab , Wang Zhong , Garraway Levi , Hahn William , Roberts Charles 
Published: May 2015

Abstract
Cancer genome sequencing efforts have revealed that ARID1A is frequently mutated in many types of cancer. Inactivating mutations occur in 45% of ovarian clear cell and endometrioid carcinomas, 19% of gastric cancers, 19% of bladder cancers, 14% of hepatocellular cancers, 12% of melanomas, and less frequently in colorectal, lung, breast and pancreatic cancers. ARID1A has also been validated as having bona fide tumor suppressor properties. Consequently, identification of specific vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. We therefore performed a systematic search for genetic vulnerabilities created by ARID1A mutation. Out of 9000+ genes screened, ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, was the number one gene preferentially required in ARID1A-mutant cancer cells. In validation studies, we find that knockdown of ARID1B indeed specifically impairs the proliferation of ARID1A-mutant cancer cell lines. Mechanistically, we show that loss of ARID1B in ARID1A-mutant cancer cell lines destabilizes the SWI/SNF complex and results in dissociation of the catalytic ATPase subunit SMARCA4. We further show that this finding also holds true in primary murine fibroblasts genetically engineered conditional for ARID1A. Our findings demonstrate that cancer cell lines harboring mutations in ARID1A are specifically dependent upon ARID1B and provide insight into the structural role of ARID1A/B in the SWI/SNF complex. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that all ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. These results also indicate that ARID1B could be considered a potential therapeutic target for the wide variety of ARID1A-mutant human cancers.
[K.H. and X.W contributed equally to this work.]
Citation Format: Katherine Helming, Xiaofeng Wang, Boris Wilson, Francisca Vazquez, Jeffrey Haswell, Haley Manchester, Youngha Kim, Gregory V. Kryukov, Mahmoud Ghandi, Andrew J. Aguirre, Zainab Jagani, Zhong Wang, Levi Garraway, William Hahn, Charles Roberts. ARID1B is a specific vulnerability in ARID1A-mutant cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-126. doi:10.1158/1538-7445.AM2014-LB-126
Abstract LB-131: Elevated (L) -2-hydroxyglutarate promotes loss of 5-hydroxymethylcytosine in clear cell renal cancer
Authors: Shim Eun-Hee , Livi Carolina B. , Knight John , Holmes Ross P. , Rakheja Dinesh , Velu Sadanan , Kho Eun-Young , Chenna Balachandra , Rea Shane L. , Benson Daniel , Kirkman Richard , Ghosh Arindam , Li Qiuhua , Bae Sejong , Wei Shi , Block Karen L. , Sudarshan Sunil 
Published: May 2015

Abstract
We undertook an unbiased metabolomics profile of clear cell renal cell carcinoma (ccRCC), the most common histological subtype, to gain deeper insight into the metabolic basis of this disease. Here, we demonstrate elevations of the metabolite 2-hydroxyglutarate (2HG) in kidney cancer. Elevation of 2HG, specifically the D- enantiomer, has been linked to transformation and identified in the context of gain of function mutations of isocitrate dehydrogenase (IDH1 and IDH2). Notably, enantiomeric resolution demonstrates that, in contrast to IDH1/IDH2 mutant tumors, kidney tumors demonstrate elevations of the L enantiomer of 2HG (L-2HG). Moreover, high 2HG tumors demonstrate reduced DNA levels of 5-hydroxymethylcytosine (5hmC) consistent with the ability of L-2HG to inhibit TET (Ten Eleven Translocation) enzymes which convert 5-methylcystoine to 5-hmC. Finally, we demonstrate that these changes are mediated by the reduced expression of L-2HG dehydrogenase (L2HGDH) in ccRCC.
Here, we report elevations of the putative oncometabolite L-2HG in the most common subtype of kidney cancer and describe a novel mechanism for the regulation of DNA 5hmC levels. Our findings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer.
Citation Format: Eun-Hee Shim, Carolina B. Livi, John Knight, Ross P. Holmes, Dinesh Rakheja, Sadanan Velu, Eun-Young Kho, Balachandra Chenna, Shane L. Rea, Daniel Benson, Richard Kirkman, Arindam Ghosh, Qiuhua Li, Sejong Bae, Shi Wei, Karen L. Block, Sunil Sudarshan. Elevated (L) -2-hydroxyglutarate promotes loss of 5-hydroxymethylcytosine in clear cell renal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-131. doi:10.1158/1538-7445.AM2014-LB-131
Abstract LB-133: Orchestrated recruitment of histone methyltransferases to DNA double strand breaks facilitates 53BP1 binding and proficient repair
Authors: Tuzon Creighton T. , Spektor Tanya M. , Congdon Lauren M. , Kong Xiaodong , Cheung Peggie , Kuo Alex J. , Yokomori Kyoko , Gozani Or , Rice Judd C. 
Published: May 2015

Abstract
While selective binding of the tandem tudor domains of p53 binding protein 1 (53BP1) to dimethylated histone H4 lysine 20 (H4K20me2) at DNA double strand breaks (DSBs) is well-documented to be an essential event for proficient DSB repair, the enzyme(s) responsible for H4K20 methylation at DSBs remained unknown. Contrary to previous reports implicating the MMSET/NSD2 methyltransferase in this pathway, we demonstrate that MMSET is dispensable for H4K20 methylation, 53BP1 accumulation and DSB repair. Alternatively, we discovered that the PR-Set7 H4K20 monomethyltransferase (H4K20me1) is an essential component of nonhomologous end joining (NHEJ) which functions early and directly in DSB repair. PR-Set7 was found to mobilize immediately to DSBs and PR-Set7 enzymatic activity was necessary for H4K20 methylation, 53BP1 accumulation and proficient DSB repair. Identification of PR-Set7-associated proteins revealed interactions between PR-Set7 and several NHEJ repair proteins. Consistent with these findings, the rapid recruitment of PR-Set7 to induced DSBs was dependent on direct binding to the NHEJ Ku70/Ku86 heterodimer. PR-Set7-mediated H4K20me1 was found to be necessary, but not sufficient, for H4K20me2 and 53BP1 recruitment at induced DSBs and an undamaged ectopic locus. In addition, we also discovered that the Suv4-20 H4K20 dimethyltransferases mobilize to DSBs and were required for H4K20me2 and 53BP1 accumulation. Importantly, Suv4-20 was not sufficient for H4K20me2 and 53BP1 localization at induced DSBs or an undamaged ectopic locus in cells lacking a catalytically competent PR-Set7. Therefore, these results illuminate an orchestrated molecular pathway whereby PR-Set7-mediated H4K20me1 “primes” the DSB to expedite subsequent catalysis by Suv4-20 for the generation of H4K20me2 at the lesion necessary for 53BP1 binding. The collective findings identify PR-Set7 as an essential early component of NHEJ and reveal a novel temporal PR-Set7-dependent pathway that facilitates H4K20me2 and 53BP1 accumulation at DSBs necessary for proficient DSB repair. Furthermore, these results and preliminary studies indicate that small molecule inhibitors targeting PR-Set7 and/or Suv4-20 will likely be clinically effective radio- and chemo-sensitizing agents in cancer treatment.
Citation Format: Creighton T. Tuzon, Tanya M. Spektor, Lauren M. Congdon, Xiaodong Kong, Peggie Cheung, Alex J. Kuo, Kyoko Yokomori, Or Gozani, Judd C. Rice. Orchestrated recruitment of histone methyltransferases to DNA double strand breaks facilitates 53BP1 binding and proficient repair. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-133. doi:10.1158/1538-7445.AM2014-LB-133
Abstract LB-145: Astrocytes directly influence tumor cell invasion and metastasis in vivo
Authors: Wang Ling , Cossette Stephanie , Rarick Kevin , Gershan Jill , Michael Michael , Harder David , Ramchandran Ramani 
Published: May 2015

Abstract
Brain metastasis is a defining component of tumor pathophysiology, and the underlying mechanisms responsible for this phenomenon are not well understood. Current dogma is that tumor cells stimulate and activate astrocytes, and this mutual relationship is critical for tumor cell sustenance in the brain. Here, we provide evidence that primary rat neonatal and adult astrocytes secrete factors that proactively induced human lung and breast tumor cell invasion and metastasis capabilities. Among which, tumor invasion factors namely matrix metalloprotease-2 (MMP-2) and MMP-9 were partly responsible for the astrocyte media-induced tumor cell invasion. Inhibiting MMPs reduced the ability of tumor cell to migrate and invade in vitro. Further, injection of astrocyte media-conditioned breast cancer cells in mice showed increased invasive activity to the brain and other distant sites. More importantly, blocking the preconditioned tumor cells with broad spectrum MMP inhibitor decreased the invasion and metastasis of the tumor cells, in particular to the brain in vivo. Collectively, our data implicate astrocyte-derived MMP-2 and MMP-9 as critical players that facilitate tumor cell migration and invasion leading to brain metastasis.
Citation Format: Ling Wang, Stephanie Cossette, Kevin Rarick, Jill Gershan, Michael Michael, David Harder, Ramani Ramchandran. Astrocytes directly influence tumor cell invasion and metastasis in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-145. doi:10.1158/1538-7445.AM2014-LB-145
Abstract LB-148: Inflammatory cytokines alter the sensitivity of breast cancer cells to endocrine treatments
Authors: Stender Joshua D. , Kastrati Irida , Yakir Maayan , Frasor Jonna , Glass Christopher K. 
Published: May 2015

Abstract
In breast cancer, infiltration of macrophages establishes an inflammatory tumor microenvironment, which can foster an extremely aggressive and therapy resistant tumor. Although inflammatory cytokines are known to modulate the transcriptional potential of estrogens and contribute to an endocrine-resistant state in cell-based model systems, the underlying molecular mechanisms remain poorly defined. We have used the human breast cancer cell-line MCF-7, an estrogen receptor α(ERα) positive and inflammatory cytokine sensitive cell line, to define the global impact inflammatory cytokines on the ERα cistrome and ERα-dependent transcriptional activity using next-generation sequencing methods. IL-1β and TNFα treatments establish an ERα cistrome that substantially overlaps with the E2-dependent ERα cistrome and results in ERα-dependent, ligand-independent activation of gene expression. Cytokine stimulation of MCF-7 cells results in phosphorylation of ERα at S305 which drives the ligand-independent activation of ERα. Pharmacological inhibition of IKKα/β blocks cytokine-dependent S305 phosphorylation, inhibits the cytokine-dependent ERα cistome, and abolishes cytokine-dependent gene activation. Additionally, S305 phosphorylation by cytokine treatments blocks the ability of tamoxifen to inhibit the expression of a subset of E2-dependent target genes and mutation of S305 to alanine restores tamoxifen sensitivity in the presence of IL-1β or TNFα. Collectively, these results provide molecular details dictating how inflammatory cytokines activate the transcriptional potential of ERα and drive an endocrine-resistant state in human breast cancer cells. In addition, they highlight the potential for anti-inflammatory therapies to be utilized in the treatment of patients with tamoxifen-resistant breast cancer.
Citation Format: Joshua D. Stender, Irida Kastrati, Maayan Yakir, Jonna Frasor, Christopher K. Glass. Inflammatory cytokines alter the sensitivity of breast cancer cells to endocrine treatments. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-148. doi:10.1158/1538-7445.AM2014-LB-148
Abstract LB-153: Influence of macrophages and p38α/β signaling on early metastatic dissemination of premalignant ErbB2+ mammary epithelial cells
Authors: Linde Nina , Mortha Arthur , Sosa Soledad , Merad Miriam , Aguirre-Ghiso Julio 
Published: May 2015

Abstract
Metastases originate from tumor cells that disseminate from the primary site through a process aided by macrophages. This was proposed to occur only during late invasive stages of cancer. However, the presence of tumor cells in the bone marrow of patients with ductal carcinoma in situ (DCIS), a pre-invasive form of breast cancer, argues that these events can take place earlier. The mechanisms driving this process are poorly understood. Our lab showed that in the MMTV-ErbB2 breast cancer model, inhibition of p38 signaling accelerated disease progression and enhances early dissemination. Using this same model and knowing that macrophages are key for mammary gland development and remodeling, we investigated whether these inflammatory cells might actively participate in early dissemination. We now show that F4/80+ macrophages associate with mammary ducts in the periphery of the myoepithelial layer but are never inside the ducts in wild type or in pre-malignant 18-20 week old MMTV-ErbB2 mice mammary glands. We found that macrophages are recruited into epithelial layers of pre-malignant lesions, when the ErbB2 oncogene is amplified and p38 activity is lost. This event showed a high correlation with enhanced dissemination of ErbB2+CK8/18+ mammary epithelial cells (MECs) detected in circulation or the bone marrow. Sites where macrophages had invaded the ducts showed disruption of the myoepithelium and reduced E-Cadherin expression in MECs. Depletion of macrophages from pre-malignant MMTV-Neu mice abolished p38 driven early dissemination. Importantly, DCIS samples from patients frequently contained intra-epithelial macrophages. These data suggest that macrophages may actively aid early dissemination from pre-malignant tissue, but only in the context of p38 inhibition and ErbB2 activation. Further, in areas of macrophage infiltration, luminal ductal cells may downregulate E-cadherin, which could foster cell migration/invasion. Our data in human DCIS samples further underscores the relevance of our findings and indicates that analysis of macrophages in DCIS lesions might be useful to better identify patients at high risk of carrying disseminated disease.
Citation Format: Nina Linde, Arthur Mortha, Soledad Sosa, Miriam Merad, Julio Aguirre-Ghiso. Influence of macrophages and p38α/β signaling on early metastatic dissemination of premalignant ErbB2+ mammary epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-153. doi:10.1158/1538-7445.AM2014-LB-153
Abstract LB-159: Characterization of cell-cycle progression using a novel bi-cistronic lentiviral FUCCI reporter
Authors: Pineda Gabriel , Lambert-Fliszar Florence , Riso Gennarina L. , Kane Kathleen M. , Jamieson Catriona 
Published: May 2015

Abstract
Currently, there are few methods to visualize cell cycle progression in leukemia stem cells (LSC). Human LSC are characterized as quiescent self-renewing cells that drive leukemic transformation of myeloproliferative neoplasms and myelodysplastic syndromes. Additionally, current methods require sequential transduction and clonal selection. These methods and conditions are not feasible to study primary patient samples and LSC, which are generally limited in sample size. To alleviate this challenge, we generated a lentiviral biscistronic vector encoding FUCCI (fluorescent ubiquitination-based cell-cycle indicator) probes. Time-lapse confocal imaging of transduced 293 cells and SKNO-1 cells exhibited normal cell division and distinct nuclear staining of either green or red fluorescence. Further, analysis by flow cytometry of 293 cell confirms that S/G2/M and G1/G0 phases of cell cycle correlate to expression of fluorescent reporters expressed from bicistronic lentiviral vector and recapitulate FACS plots using traditional Ki67 and 7AAD staining. The development of this new reagent offers a new and more effective method to track cell cycle progression in limited mammalian cell populations. Future studies will utilize primary patient CD34+CD38- selected leukemic stem cell populations.
Citation Format: Gabriel Pineda, Florence Lambert-Fliszar, Gennarina L. Riso, Kathleen M. Kane, Catriona Jamieson. Characterization of cell-cycle progression using a novel bi-cistronic lentiviral FUCCI reporter. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-159. doi:10.1158/1538-7445.AM2014-LB-159
Abstract LB-162: Translational imaging of tumorigenesis in a TP53 porcine cancer model
Authors: Sieren Jessica C. , Wang Xiao-Jun , Davis Bryan , Newell John D. , Hammond Emily , Rohret Judy , Rohret Frank , Struzynski Jason , Goeken Adam , Naumann Paul , Leidinger Mariah , Hagen Jussara , Rheeden Richard Van , Darbro Benjamin W. , Quelle Dawn E. , Meyerholz David K. , Rogers Christopher S. 
Published: May 2015

Abstract
Cancer remains the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer have been informative but also present challenges to translating promising imaging approaches and therapies to the clinic. The lack of a large animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools and interventions (surgical and therapeutic). This study sought to 1) develop a genetically-modified porcine model of cancer expressing a TP53 mutation commonly found in humans (R175H in people, R167H in pigs), 2) validate the cellular p53 mutation and 3) evaluate tumor development in the animals using medical imaging, histopathology and molecular approaches. TP53R167H/R167H mutant pigs primarily developed lymphomas and osteogenic tumors, mimicking the tumor types observed in mice and humans expressing the orthologous TP53 mutant allele. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathologic evaluation following necropsy. Molecular genetic analyses confirmed mutant p53 expression and characteristic chromosomal instability within the tumors. In conclusion, TP53R167H/R167H pigs provide a novel large animal tumor model that replicates the human condition and is uniquely suited to developing clinically-relevant, non-invasive imaging approaches to facilitate earlier detection, diagnosis and treatment of human cancers.
Citation Format: Jessica C. Sieren, Xiao-Jun Wang, Bryan Davis, John D. Newell, Emily Hammond, Judy Rohret, Frank Rohret, Jason Struzynski, Adam Goeken, Paul Naumann, Mariah Leidinger, Jussara Hagen, Richard Van Rheeden, Benjamin W. Darbro, Dawn E. Quelle, David K. Meyerholz, Christopher S. Rogers. Translational imaging of tumorigenesis in a TP53 porcine cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-162. doi:10.1158/1538-7445.AM2014-LB-162
Abstract LB-167: Tumor cells, but not endothelial cells, mediate the eradication of primary cancers by radiation therapy
Authors: Moding Everett J. , Lee Chang-Lung , Castle Katherine D. , Oh Patrick , Kirsch David G. 
Published: May 2015

Abstract
Radiation therapy is frequently utilized in the clinic as curative treatment for cancers, but the contribution of endothelial cells to tumor response to radiation remains controversial. Using the two highly efficient site-specific recombinases, Cre and FlpO, we have generated primary tumors in mice with different gene mutations specifically in tumor cells and stromal cells. With this dual recombinase technology, we selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. We found that deletion of Bax in endothelial cells did not affect tumor response to radiation, but Atm deletion increased radiation-induced death of tumor endothelial cells and prolonged tumor growth delay following a non-curative dose of radiation. However, following a curative dose of radiation, Atm deletion in endothelial cells did not affect growth delay of primary tumors and failed to increase local control. In contrast, deletion of Atm in tumor cells increased local control of primary tumors by radiation therapy. These results demonstrate that tumor cells rather than endothelial cells are the critical targets that regulate tumor eradication by radiation therapy. They also emphasize the importance of using primary models of cancer to study the role of stromal cells in tumor development and response to therapy.
Citation Format: Everett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, David G. Kirsch. Tumor cells, but not endothelial cells, mediate the eradication of primary cancers by radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-167. doi:10.1158/1538-7445.AM2014-LB-167